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Nanotechnology

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Nanotechnology encompasses the understanding of the fundamental physics, chemistry, biology and technology of nanometre-scale objects.

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Raffi Budakian et al 2024 Nanotechnology 35 412001

The field of nanoscale magnetic resonance imaging (NanoMRI) was started 30 years ago. It was motivated by the desire to image single molecules and molecular assemblies, such as proteins and virus particles, with near-atomic spatial resolution and on a length scale of 100 nm. Over the years, the NanoMRI field has also expanded to include the goal of useful high-resolution nuclear magnetic resonance (NMR) spectroscopy of molecules under ambient conditions, including samples up to the micron-scale. The realization of these goals requires the development of spin detection techniques that are many orders of magnitude more sensitive than conventional NMR and MRI, capable of detecting and controlling nanoscale ensembles of spins. Over the years, a number of different technical approaches to NanoMRI have emerged, each possessing a distinct set of capabilities for basic and applied areas of science. The goal of this roadmap article is to report the current state of the art in NanoMRI technologies, outline the areas where they are poised to have impact, identify the challenges that lie ahead, and propose methods to meet these challenges. This roadmap also shows how developments in NanoMRI techniques can lead to breakthroughs in emerging quantum science and technology applications.

Attila Géczy et al 2024 Nanotechnology 35 435201

In this paper, we present a novel polylactic-acid/flax-composite substrate and the implementation of a demonstrator: a microcontroller board based on commercial design. The substrate is developed for printed circuit board (PCB) applications. The pre-preg is biodegradable, reinforced, and flame-retarded. The novel material was developed to counter the increasing amount of e-waste and to improve the sustainability of the microelectronics sector. The motivation was to present a working circuit in commercial complexity that can be implemented on a rigid substrate made of natural, bio-based materials with a structure very similar to the widely used Flame Retardant Class 4 (FR4) substrate at an early technological readiness level (2–3). The circuit design is based on the Arduino Nano open-source microcontroller board design so that the demonstration could be programmable and easy to fit into education, IoT applications, and embedded designs. During the work, the design was optimized at the level of layout. The copper-clad pre-preg was then prepared and processed with subtractive printed wiring technology and through hole plating. The traditional surface mounting methodology was applied for assembly. The resulting yield of PCB production was around 50%. Signal analysis was successful with analogue data acquisition (voltage) and low-frequency (4 kHz) tests, indistinguishable from sample FR4 boards. Eventually, the samples were subjected to highly accelerated stress test (HAST). HAST tests revealed limitations compared to traditional FR4 printed circuit materials. After six cycles, the weight loss was around 30% in the case of PLA/Flax, and as three-point bending tests showed, the possible ultimate strength (25 MPa at a flexural state) was reduced by 80%. Finally, the sustainability aspect was assessed, where we found that ∼95 vol% and ∼90 wt% of the traditional substrate can be substituted, significantly easing the load of waste on the environment.

Thiago A S L Sousa et al 2024 Nanotechnology 35 425503

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), etiological agent for the coronavirus disease 2019 (COVID-19), has resulted in over 775 million global infections. Early diagnosis remains pivotal for effective epidemiological surveillance despite the availability of vaccines. Antigen-based assays are advantageous for early COVID-19 detection due to their simplicity, cost-effectiveness, and suitability for point-of-care testing (PoCT). This study introduces a graphene field-effect transistor-based biosensor designed for high sensitivity and rapid response to the SARS-CoV-2 spike protein. By functionalizing graphene with monoclonal antibodies and applying short-duration gate voltage pulses, we achieve selective detection of the viral spike protein in human serum within 100  µ s and at concentrations as low as 1 fg ml −1 , equivalent to 8 antigen molecules per µ l of blood. Furthermore, the biosensor estimates spike protein concentrations in serum from COVID-19 patients. Our platform demonstrates potential for next-generation PoCT antigen assays, promising fast and sensitive diagnostics for COVID-19 and other infectious diseases.

Jamil K Jadoon and Phuong V Pham 2024 Nanotechnology 35 435706

This study describes the fabrication of composite electrodes comprising TiO 2 and reduced graphene oxide layers using a moderate-temperature hydrothermal method. The morphology, crystalline structure, chemical composition, and optical features of the prepared composites were analyzed by FE-SEM, x-ray diffraction, FTIR, and UV–visible spectroscopy. The cyclic voltammetry (CV) and Nyquist plots were used to assess the electrochemical and impedance responses of the composite electrodes, respectively. The analysis revealed that the incorporation of RGO reduced the TiO 2 bandgap to 3.87 eV 3.02 eV and improved the specific capacitance, enhancing the TiO 2 -RGO electrode's supercapacitive performance. CV studies highlight that the TiO 2 -RGO composite has a high specific capacitance of 152 F g −1 at a substantially faster scan rate of 25 mV s −1 in a 1.0 M-KOH dilute electrolyte. These findings confirmed the applicability of the fabricated electrodes as prospective supercapacitor electrodes.

Karl Berggren et al 2021 Nanotechnology 32 012002

Recent progress in artificial intelligence is largely attributed to the rapid development of machine learning, especially in the algorithm and neural network models. However, it is the performance of the hardware, in particular the energy efficiency of a computing system that sets the fundamental limit of the capability of machine learning. Data-centric computing requires a revolution in hardware systems, since traditional digital computers based on transistors and the von Neumann architecture were not purposely designed for neuromorphic computing. A hardware platform based on emerging devices and new architecture is the hope for future computing with dramatically improved throughput and energy efficiency. Building such a system, nevertheless, faces a number of challenges, ranging from materials selection, device optimization, circuit fabrication and system integration, to name a few. The aim of this Roadmap is to present a snapshot of emerging hardware technologies that are potentially beneficial for machine learning, providing the Nanotechnology readers with a perspective of challenges and opportunities in this burgeoning field.

Narine Moses Badlyan et al 2024 Nanotechnology 35 435001

The optical properties of the direct-bandgap transition metal dichalcogenides (TMDCs) MoS 2 and WS 2 are heavily influenced by their atomic defect structure and substrate interaction. In this work we use low-voltage chromatic and spherical aberration (C C /C S )-corrected high-resolution transmission electron microscopy to simultaneously create and image chalcogen vacancies in TMDCs. However, correlating the defect structure, produced and analyzed using transmission electron microscopy (TEM), with optical spectroscopy often presents challenges because of very different fields of view and sample platforms involved. Here we employ a reverse transfer technique to transfer electron-irradiated single-layer MoS 2 and WS 2 from the TEM grid to various substrates for subsequent optical examination. The dynamics of defect creation are studied in atomic resolution on a separate sample, which allows to apply the derived statistics to larger irradiated areas on the other samples. The intensity of both the defect-bound exciton peak in photoluminescence (PL) and the defect-induced LA (M) mode in Raman spectra increase with defect density. The best substrates for defect-density determination by optical spectroscopy are polystyrene for PL and SiC and Si/SiO 2 for Raman spectroscopy. These investigations represent an important step towards the quantification of defects using solely optical spectroscopy, paving the way for fast, reliable, and automatable optical quality control of optoelectronic devices.

David Cooper et al 2024 Nanotechnology 35 435206

Here we use off-axis electron holography combined with advanced transmission electron microscopy techniques to understand the opto-electronic properties of AlGaN tunnel junction (TJ)-light-emitting diode (LED) devices for ultraviolet emission. Four identical AlGaN LED devices emitting at 290 nm have been grown by metal–organic chemical vapour deposition. Then Ge doped n-type regions with and without InGaN or GaN interlayers (IL) have been grown by molecular beam epitaxy onto the top Mg doped p-type layer to form a TJ and hence a high quality ohmic metal contact. Off-axis electron holography has then been used to demonstrate a reduction in the width of the TJ from 9.5 to 4.1 nm when an InGaN IL is used. As such we demonstrate that off-axis electron holography can be used to reproducibly measure nm-scale changes in electrostatic potential in highly defected and challenging materials such as AlGaN and that systematic studies of devices can be performed. The LED devices are then characterized using standard opto-electric techniques and the improvements in the performance of the LEDs are correlated with the electron holography results.

Yi-Teng Huang et al 2021 Nanotechnology 32 132004

Lead-halide perovskites have demonstrated astonishing increases in power conversion efficiency in photovoltaics over the last decade. The most efficient perovskite devices now outperform industry-standard multi-crystalline silicon solar cells, despite the fact that perovskites are typically grown at low temperature using simple solution-based methods. However, the toxicity of lead and its ready solubility in water are concerns for widespread implementation. These challenges, alongside the many successes of the perovskites, have motivated significant efforts across multiple disciplines to find lead-free and stable alternatives which could mimic the ability of the perovskites to achieve high performance with low temperature, facile fabrication methods. This Review discusses the computational and experimental approaches that have been taken to discover lead-free perovskite-inspired materials, and the recent successes and challenges in synthesizing these compounds. The atomistic origins of the extraordinary performance exhibited by lead-halide perovskites in photovoltaic devices is discussed, alongside the key challenges in engineering such high-performance in alternative, next-generation materials. Beyond photovoltaics, this Review discusses the impact perovskite-inspired materials have had in spurring efforts to apply new materials in other optoelectronic applications, namely light-emitting diodes, photocatalysts, radiation detectors, thin film transistors and memristors. Finally, the prospects and key challenges faced by the field in advancing the development of perovskite-inspired materials towards realization in commercial devices is discussed.

Osman Sahin et al 2024 Nanotechnology 35 395301

Electron beam lithography (EBL) stands out as a powerful direct-write tool offering nanometer-scale patterning capability and is especially useful in low-volume R&D prototyping when coupled with pattern transfer approaches like etching or lift-off. Among pattern transfer approaches, lift-off is preferred particularly in research settings, as it is cost-effective and safe and does not require tailored wet/dry etch chemistries, fume hoods, and/or complex dry etch tools; all-in-all offering convenient, 'undercut-free' pattern transfer rendering it useful, especially for metallic layers and unique alloys with unknown etchant compatibility or low etch selectivity. Despite the widespread use of the lift-off technique and optical/EBL for micron to even sub-micron scales, existing reports in the literature on nanofabrication of metallic structures with critical dimension in the 10–20 nm regime with lift-off-based EBL patterning are either scattered, incomplete, or vary significantly in terms of experimental conditions, which calls for systematic process optimization. To address this issue, beyond what can be found in a typical photoresist datasheet, this paper reports a comprehensive study to calibrate EBL patterning of sub-50 nm metallic nanostructures including gold nanowires and nanogaps based on a lift-off process using bilayer polymethyl-methacrylate as the resist stack. The governing parameters in EBL, including exposure dose, soft-bake temperature, development time, developer solution, substrate type, and proximity effect are experimentally studied through more than 200 EBL runs, and optimal process conditions are determined by field emission scanning electron microscope imaging of the fabricated nanostructures reaching as small as 11 nm feature size.

Aleksander Cholewinski et al 2024 Nanotechnology 35 395706

Microplastics (MPs) and nanoplastics have been an emerging global concern, with hazardous effects on plant, animal, and human health. Their small size makes it easier for them to spread to various ecosystems and enter the food chain; they are already widely found in aqueous environments and within aquatic life, and have even been found within humans. Much research has gone into understanding micro-/nanoplastic sources and environmental fate, but less work has been done to understand their degradation. Photocatalytic degradation is a promising green technique that uses visible or ultraviolet light in combination with photocatalyst to degrade plastic particles. While complete degradation, reducing plastics to small molecules, is often the goal, partial degradation is more common. We examined microscale polyethylene (PE) (125–150 µ m in diameter) and nanoscale polystyrene (PS) (∼300 nm in diameter) spheres both before and after degradation using multiple imaging techniques, especially electron tomography in addition to conventional electron microscopy. Electron tomography is able to image the 3D exterior and interior of the nanoplastics, enabling us to observe within aggregates and inside degraded spheres, where we found potentially open interior structures after degradation. These structures may result from differences in degradation and aggregation behavior between the different plastic types, with our work finding that PE MPs typically cracked into sharp fragments, while PS nanoplastics often fragmented into smoother, more curved shapes. These and other differences, along with interior and 3D surface images, provide new details on how the structure and aggregation of PE MPs and PS nanoplastics changes when degraded, which could influence how the resulting worn particles are collected or treated further.

Latest articles

R Archana B Mohapatra et al 2024 Nanotechnology 35 455702

In pursuing advanced neuromorphic applications, this study introduces the successful engineering of a flexible electronic synapse based on WO 3− x , structured as W/WO 3− x /Pt/Muscovite-Mica. This artificial synapse is designed to emulate crucial learning behaviors fundamental to in-memory computing. We systematically explore synaptic plasticity dynamics by implementing pulse measurements capturing potentiation and depression traits akin to biological synapses under flat and different bending conditions, thereby highlighting its potential suitability for flexible electronic applications. The findings demonstrate that the memristor accurately replicates essential properties of biological synapses, including short-term plasticity (STP), long-term plasticity (LTP), and the intriguing transition from STP to LTP. Furthermore, other variables are investigated, such as paired-pulse facilitation, spike rate-dependent plasticity, spike time-dependent plasticity, pulse duration-dependent plasticity, and pulse amplitude-dependent plasticity. Utilizing data from flat and differently bent synapses, neural network simulations for pattern recognition tasks using the Modified National Institute of Standards and Technology dataset reveal a high recognition accuracy of ∼95% with a fast learning speed that requires only 15 epochs to reach saturation.

Yiming Zhang et al 2024 Nanotechnology 35 455701

Low-cost, highly efficient thermoelectric thin-film materials are becoming increasingly popular as miniaturization progresses. Mg 3 Sb 2 has great potential due to its low cost and high performance. However, the fabrication of Mg 3 Sb 2 thin films with high power factors (PFs) poses a certain challenge. In this work, we propose a general approach to prepare Mg 3 Sb 2 thin films with excellent thermoelectric properties. Using a two-step thermal evaporation and rapid annealing process, (001)-oriented Mg 3 Sb 2 thin films are fabricated on c -plane-oriented Al 2 O 3 substrates. The structure of the film orientation is optimized by controlling the film thickness, which modulates the thermoelectric performance. The PF of the Mg 3 Sb 2 at 500 nm (14 μ W·m −1 ·K −2 ) would increase to 169 μ W·m −1 ·K −2 with Ag doping (Mg 3 Ag 0.02 Sb 2 ) at room temperature. This work provides a new strategy for the development of high-performance thermoelectric thin films at room temperature.

Xuan Xu et al 2024 Nanotechnology 35 455202

Scalable production of reduced graphene oxide (rGO) films with high mechanical-electrical properties is desirable as these films are candidates for wearable electronics devices and energy storage applications. Removing structural incompleteness such as wrinkles or voids in the graphene films, which are generated from the assembly process, would greatly optimize their mechanical properties. However, the densely stacked graphene sheets in the films degrade their ionic kinetics and thus limit their development. Here, a horizontal-longitudinal-structure modulating strategy is demonstrated to produce enhanced mechanical, conductive, and capacitive graphene films. Typically, two-dimensional large graphene sheets (LGS) induce regular stacking of graphene oxide (GO) during the assembly process to reduce wrinkles, while one-dimensional single-walled carbon nanotubes (SWCNT) bridge with graphene sheets to strengthen the multidirectional intercalation and reduce GO layer restacking. The simultaneous incorporation of LGS and SWCNT synergistically creates a fine microstructure by improving the alignment of graphene sheets, increasing continuous conductive pathways to facilitate electron transport, and enlarging interlayer spacing to promote electrolyte ion diffusion. As a result, the obtained graphene films are flat and exhibit signally reinforced mechanical properties, electrical conductivity (38727 S m −1 ), as well as specific capacitance (232 F g −1 ) as supercapacitor electrodes compared to those of original rGO films. Moreover, owing to the comprehensive improved properties, a flexible gel supercapacitor assembled by the graphene film-based electrodes shows high energy density, good flexibility, and excellent cycling stability (93.8% capacitance retention after 10 000 cycles). This work provides a general strategy to manufacture robust graphene structural materials for energy storage applications in flexible and wearable electronics.

Abigail A Conner et al 2024 Nanotechnology 35 455101

The expansion of pluripotent stem cells (PSCs) in vitro remains a critical barrier to their use in tissue engineering and regenerative medicine. Biochemical methods for PSC expansion are known to produce heterogeneous cell populations with varying states of pluripotency and are cost-intensive, hindering their clinical translation. Engineering biomaterials to physically control PSC fate offers an alternative approach. Surface or substrate topography is a promising design parameter for engineering biomaterials. Topographical cues have been shown to elicit profound effects on stem cell differentiation and proliferation. Previous reports have shown isotropic substrate topographies to be promising in expanding PSCs. However, the optimal feature to promote PSC proliferation and the pluripotent state has not yet been determined. In this work, the MultiARChitecture (MARC) plate is developed to conduct a high-throughput analysis of topographical cues in a 96-well plate format. The MARC plate is a reproducible and customizable platform for the analysis of multiple topographical patterns and features and is compatible with both microscopic assays and molecular biology techniques. The MARC plate is used to evaluate the expression of pluripotency markers Oct4, Nanog , and Sox2 and the differentiation marker LmnA as well as the proliferation of murine embryonic stem (mES) cells. Our systematic analyses identified three topographical patterns that maintain pluripotency in mES cells after multiple passages: 1 µ m pillars (1 µ m spacing, square arrangement), 2 µ m wells (c-c ( x, y ) = 4, 4 µ m), and 5 µ m pillars (c-c ( x, y ) = 7.5, 7.5 µ m). This study represents a step towards developing a biomaterial platform for controlled murine PSC expansion.

Chen Chong et al 2024 Nanotechnology 35 455201

In order to predict the single particle irradiation of tunnel field effect transistor (TFET) devices, a deep learning algorithm network model was built to predict the key characterization parameters of the single particle transient. Computer aided design (TCAD) technique is used to study the influence of single particle effect on the novel stacked source trench gate TFET device. The results show that with the increase of drain voltage, incident width of heavy ions (less than 0.04 μ m), and linear energy transfer, the drain transient current and collected charge also increase. The prediction results of deep learning algorithm show that the relative error percentage of drain current pulse peak ( I DMAX ) and collected charge ( Q c ) is less than 10%, and the relative error percentage of most predicted values is less than 1%. Comparison experiments with five traditional machine learning methods (support vector machine, decision tree, K-nearest algorithm, ridge regression, linear regression) show that the deep learning algorithm has the best performance and has the smallest average error percentage. This data-driven deep learning algorithm model not only enables researchers who are not familiar with semiconductor devices to quickly obtain the transient data of a single particle under any conditions; at the same time, it can be applied to digital circuit design as a data-driven device model reflecting the reliability of single particle transient. The application of deep learning in the field of device irradiation prediction has a highly promising prospect in the future.

Review articles

Guojie Chao et al 2024 Nanotechnology 35 432001

Ammonia (NH 3 ) is a versatile and important compound with a wide range of uses, which is currently produced through the demanding Haber-Bosch process. Electrocatalytic nitrate reduction into ammonia (NRA) has recently emerged as a sustainable approach for NH 3 synthesis under ambient conditions. However, the NRA catalysis is a complex multistep electrochemical process with competitive hydrogen evolution reaction that usually results in poor selectivity and low yield rate for NH 3 synthesis. With maximum atom utilization and well-defined catalytic sites, single atom catalysts (SACs) display high activity, selectivity and stability toward various catalytic reactions. Very recently, a number of SACs have been developed as promising NRA electrocatalysts, but systematical discussion about the key factors that affect their NRA performance is not yet to be summarized to date. This review focuses on the latest breakthroughs of SACs toward NRA catalysis, including catalyst preparation, catalyst characterization and theoretical insights. Moreover, the challenges and opportunities for improving the NRA performance of SACs are discussed, with an aim to achieve further advancement in developing high-performance SACs for efficient NH 3 synthesis.

Shubham Gupta et al 2024 Nanotechnology 35 423001

Silicon in its nanoscale range offers a versatile scope in biomedical, photovoltaic, and solar cell applications. Due to its compatibility in integration with complex molecules owing to changes in charge density of as-fabricated Silicon Nanostructures (SiNSs) to realize label-free and real-time detection of certain biological and chemical species with certain biomolecules, it can be exploited as an indicator for ultra-sensitive and cost-effective biosensing applications in disease diagnosis. The morphological changes of SiNSs modified receptors (PNA, DNA, etc) have huge future scope in optimized sensitivity (due to conductance variations of SiNSs) of target biomolecules in health care applications. Further, due to the unique optical and electrical properties of SiNSs realized using the chemical etching technique, they can be used as an indicator for photovoltaic and solar cell applications. In this work, emphasis is given on different critical parameters that control the fabrication morphologies of SiNSs using metal-assisted chemical etching technique (MACE) and its corresponding fabrication mechanisms focusing on numerous applications in energy storage and health care domains. The evolution of MACE as a low-cost, easy process control, reproducibility, and convenient fabrication mechanism makes it a highly reliable-process friendly technique employed in photovoltaic, energy storage, and biomedical fields. Analysis of the experimental fabrication to obtain high aspect ratio SiNSs was carried out using iMAGEJ software to understand the role of surface-to-volume ratio in effective bacterial interfacing. Also, the role of silicon nanomaterials has been discussed as effective anti-bacterial surfaces due to the presence of silver investigated in the post-fabrication energy dispersive x-ray spectroscopy analysis using MACE.

Zebin Wei et al 2024 Nanotechnology 35 402003

Benefiting from the ultrahigh specific surface areas, massive exposed surface atoms, and highly tunable microstructures, the two-dimensional (2D) noble metal nanosheets (NSs) have presented promising performance for various electrocatalytic reactions. Nevertheless, the heteroatom doping strategy, and in particular, the electronic structure tuning mechanisms of the 2D noble metal catalysts (NMCs) yet remain ambiguous. Herein, we first review several effective strategies for modulating the electrocatalytic performance of 2D NMCs. Then, the electronic tuning effect of hetero-dopants for boosting the electrocatalytic properties of 2D NMCs is systematically discussed. Finally, we put forward current challenges in the field of 2D NMCs, and propose possible solutions, particularly from the perspective of the evolution of electron microscopy. This review attempts to establish an intrinsic correlation between the electronic structures and the catalytic properties, so as to provide a guideline for designing high-performance electrocatalysts.

Ling-Wu Tong et al 2024 Nanotechnology 35 402002

Liver cancer, which is well-known to us as one of human most prevalent malignancies across the globe, poses a significant risk to live condition and life safety of individuals in every region of the planet. It has been shown that immune checkpoint treatment may enhance survival benefits and make a significant contribution to patient prognosis, which makes it a promising and popular therapeutic option for treating liver cancer at the current time. However, there are only a very few numbers of patients who can benefit from the treatment and there also exist adverse events such as toxic effects and so on, which is still required further research and discussion. Fortunately, the clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9) provides a potential strategy for immunotherapy and immune checkpoint therapy of liver cancer. In this review, we focus on elucidating the fundamentals of the recently developed CRISPR/Cas9 technology as well as the present-day landscape of immune checkpoint treatment which pertains to liver cancer. What's more, we aim to explore the molecular mechanism of immune checkpoint treatment in liver cancer based on CRISPR/Cas9 technology. At last, its encouraging and powerful potential in the future application of the clinic is discussed, along with the issues that already exist and the difficulties that must be overcome. To sum up, our ultimate goal is to create a fresh knowledge that we can utilize this new CRISPR/Cas9 technology for the current popular immune checkpoint therapy to overcome the treatment issues of liver cancer.

Accepted manuscripts

Wyndaele et al 

Due to their unique properties, two-dimensional transition metal dichalcogenides (2D TMDCs) are considered for diverse applications in microelectronics, sensing, catalysis, to name a few. A common challenge in 2D TMDC research is the film's inherent instability i.e., spontaneous oxidation upon ambient exposure. The present study systematically explores the effect aging on the film composition and photoluminescent properties of monolayer WS2, synthetically grown by metal-organic chemical vapor deposition. The aging rate is investigated for different oxygen (i.e., O2 gas concentration and humidity) and light-controlled environments. Simple mitigation strategies that do not involve capping the 2D TMDC layer are discussed, and their effectiveness demonstrated by benchmarking the evolution in photoluminescence response against ambient exposed monolayer WS2. These results highlight the need to store 2D TMDCs in controlled environments to preserve the film quality and how future studies can account for the aging effect.

Fatima et al 

Biomimetic artificial olfactory cilia have demonstrated potential in identifying specific volatile organic compounds linked to various diseases, including certain cancers, metabolic disorders, and respiratory conditions. These sensors may facilitate non-invasive disease diagnosis and monitoring. Cilia Motility is the coordinated movement of cilia, which are hair-like projections present on the surface of particular cells in different species. Cilia serve an important part in several biological functions, including motility, fluid movement, and sensory reception. Cilia motility is a complicated process that requires the coordinated interaction of structural components and molecular pathways. Cilia are made up of a highly structured structure known as the axoneme, which is made up of microtubules grouped in a unique pattern. The axoneme is made up of nine outer doublet microtubules and a core pair of singlet microtubules. This arrangement offers structural support and serves as a scaffold for the proteins involved in ciliary movement. Our latest endeavors investigate these Multiphysics phenomena in ciliary beating flows that are inspired by biology, utilizing copper, gold, and titania nanoparticles. We examine their functions in biological systems such as peristaltic transport computationally. Our models give precise two- and three-dimensional velocity, temperature, and concentration solutions by integrating transverse magnetohydrodynamics with laser heating. Furthermore, at the channel wall expressions, the skin friction coefficient, Sherwood number, Nusselt number and optimization of entropy generation are acquired and analyzed. Important properties of the velocity and scalar profiles are revealed by a thorough analysis of dimensionless parameters. The simplified examination provides more insight into the trapping patterns that result from the complex interaction between nanofluid rheology and optics. These findings greatly contribute to our knowledge and improvement of nanofluidic transport technologies in a variety of fields supporting industry, sustainability, and medicine.

Martin-Jimenez et al 

Atomic force microscopy (AFM) allows submolecular resolution imaging of organic molecules deposited on a surface by using CO-functionalized qPlus sensors under ultrahigh vacuum and low temperature conditions. However, the experimental determination of the adsorption sites of these organic molecules requires the precise identification of the atomic structure of the surface on which they are adsorbed. Here, we develop an automation method for AFM imaging that provides in a single image both, submolecular resolution on organic molecules and atomic resolution on the surrounding metallic surface. The method is based on an adaptive tunnelling current feedback system that is regulated according to the response of the AFM observables, which guarantees that both the molecules and the surface atoms are imaged under optimum conditions. Therewith, the approach is suitable for imaging adsorption sites of several adjacent and highly mobile molecules such as 2-iodotriphenylene on Ag(111) in a single scan. The proposed method with the adaptive feedback system facilitates statistical analysis of molecular adsorption geometries and could in the future contribute to autonomous AFM imaging as it adapts the feedback parameters depending on the sample properties.

Kara et al 

Drug-loaded polymeric micelles have proven to be highly effective carrier systems for the efficient delivery of hydrophobic photosensitizers in photodynamic therapy (PDT). This study introduces the micellization potential of poly(oligoethylene glycol methyl ether methacrylate) (pOEGMA) as a novel approach, utilizing the hydrophobic methacrylate segments of pOEGMA to interact with highly hydrophobic zinc phthalocyanine (ZnPc), thereby forming a potential micellar drug carrier system. The ZnPc molecule was synthesized from phthalonitrile derivatives and its fluorescence, photodegradation, and singlet oxygen quantum yields were determined in various solvents. In solvents such as tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), and N,N-dimethylformamide (DMF), the ZnPc compound exhibited the requisite photophysical and photochemical properties for PDT applications. The pOEGMA homopolymer was synthesized via reversible addition-fragmentation chain-transfer (RAFT) polymerization, while ZnPc-loaded pOEGMA micelles were prepared using the nanoprecipitation method. Characterization of the pOEGMA, ZnPc, and micelles was conducted using FTIR, 1H-NMR, dynamic light scattering (DLS), matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometries, gel permeation chromatography (GPC), and transmission electron microscopy (TEM). The critical micelle concentration (CMC) was determined to be 0.027 mg/mL using fluorescence spectrometry. The drug loading and encapsulation efficiencies of the ZnPc-loaded micelles were calculated to be 0.67% and 0.47%, respectively. Additionally, the release performance of ZnPc from pOEGMA micelles was monitored over a period of nearly 10 days, while the lyophilized micelles exhibited stability for 3 months. Lastly, the ZnPc-loaded micelles were more biocompatible than ZnPc on L929 cell line. The results suggest that the pOEGMA homopolymer possesses the capability to micellize through its methacrylate segments when interacting with highly hydrophobic molecules, presenting a promising avenue for enhancing the delivery efficiency of hydrophobic photosensitizers in PDT. Moreover, it was also deciphered that obtained formulations were highly biocompatible according to cytotoxicity results and could be safely employed as drug delivery systems in further applications.

Mao et al 

It is a challenge to improve the long-term durability of Pd-based electrocatalysts for oxygen reduction reaction (ORR) in fuel cells. Herein, Pd/CeO2-C-T (T=800, 900 and 1000℃) hybrid catalysts with metal-support interaction are prepared from Ce-based metal organic framework (Ce-MOF) precursor. Abundant tiny CeO2 nanoclusters are produced to form nanorod structures with uniformly distributed carbon through a calcination process. Meanwhile, both carbon and CeO2 nanoclusters have good contact with the following deposited surfactant-free Pd nanoclusters. Benefited from the large specific surface area, good conductivity and structure integrity, Pd/CeO2-C-900 exhibits the best electrocatalytic ORR performance: onset potential of 0.968 V and half-wave potential of 0.857 V, outperforming those obtained on Pd/C counterpart. In addition, the half-wave potential only shifts 7 mV after 6000 cycles of accelerated durability testing, demonstrating robust durability.

More Accepted manuscripts

Open access

Pieter-Jan Wyndaele et al 2024 Nanotechnology

Daniel Martin-Jimenez et al 2024 Nanotechnology

Amulya Poudyal and Bruce Tatarchuk 2024 Nanotechnology

This paper investigates a novel fiber-based filter media wherein a NaCl filtrate is collected and reservoired not only onto the surfaces of the fibers and within their inter-fiber voidage but also within the internal porosity of high pore volume nanoporous fibers or VGCF floc used to fabricate the media. This transport process is shown to occur through a NaCl dissolution into the water-filled nanopores of the fiber and a subsequent intra-fiber wicking phenomenon. The study further elucidates two distinct NaCl accommodation mechanisms which are uniquely available to filter media containing nanoporous intrafiber porosity: 1) wicking and capillary condensation of liquid NaCl aerosols directly into the intrafiber pores at high RH, and 2) dissolution of otherwise solid NaCl aerosols deposited onto fiber surfaces (at low RH) into the interior nanopores of the fiber because these pores (when hydrophilic) are saturated with water (even at low RH). To investigate these two mechanistic regimes, various media were fabricated possessing multiscale porosity in the form of: (i) embedded flocs of Vapor Grown Carbon Nanofibers (VGCFs) (4.108 cm3/gm pore volume), (ii) hydrophilic and high pore volume Activated Carbon Fibers (ACFs, 0.950 cm3/gm) and (iii) solid graphite fibers. These media were then comparatively evaluated toward NaCl aerosol filtration at different relative humidities. Pressure drop measurements versus filtrate accumulation and SEM-EDAX VGCF demonstrated the location and transport of NaCl into the intrafiber voidage. Media containing both VGCF floc and ACF accumulated 1200% more NaCl at low RH (and a specified pressure drop) than similar media prepared from non-porous graphite fibers, with an additional 315% increase from low to high RH. A Gibbs free energy driving force model is provided to illustrate the driving forces favoring water condensation into the nanopores and solid NaCl aerosol dissolution into the water phase. Filtration efficiency and Quality Factor assessments for the various media are also systematically evaluated to demonstrate the observed mechanistics.

Chuying Feng et al 2024 Nanotechnology

Bacterial vaginosis (BV) is a common vaginal infection affecting millions of women. Vaginal anaerobic dysbiosis occurs when Lactobacillus spp., the dominant flora in healthy vagina is replaced by certain overgrown anaerobes, resulting in unpleasant symptoms such as vaginal discharge and odor. With a high recurrence rate, BV also severely impacts the overall quality of life of childbearing women by inducing preterm delivery and increasing the risks of pelvic inflammatory disease and sexually transmitted infections. Among various BV-associated bacteria, Gardnerella vaginalis (G. vaginalis) has been identified as a primary pathogen since it has been isolated from almost all women carrying BV and exhibits higher virulence potential over other bacteria. When dealing with BV relapse, intravaginal drug delivery systems are superior to conventional oral antibiotic therapies in improving therapeutic efficacy owing to more effective drug dose, reduced drug resistance and minimized side effects such as stomach irritation. Traditional intravaginal drug administration generally involves solids, semi-solids and delivery devices inserted into the vaginal lumen to achieve sustained drug release. However, they are mostly designed for continuous drug release and are not preventative therapies, resulting in severe side effects caused by excess dosing. Stimuli-responsive systems that can release drug only when needed ("on-demand") can help diminish these negative side effects. Hence, we developed a bacteria-responsive liposomal platform for the prevention and treatment of BV. This platform demonstrated sustained drug release in the presence of vaginolysin (VLY), a toxin secreted specifically by G. vaginalis. We prepared four liposome formulations and evaluated their responsiveness to G. vaginalis. The results demonstrated that the liposome formulations could achieve cumulative drug release ranging from 46.7% to 51.8% over a 3-5 day period in response to G. vaginalis and hardly any drug release in the presence of Lactobacillus crispatus (L. crispatus), indicating the high specificity of the system. Overall, the bacteria-responsive drug release platform has great potential, since it will be the first time to realize sustained drug release stimulated by a specific pathogen for BV prevention and treatment. This on-demand therapy can potentially provide relief to the millions of women affected by BV.

Matteo T. A. Borghi and Neil R Wilson 2024 Nanotechnology

Photoluminescence has widely been used to study excitons in semiconducting transition metal dichalcogenide (MX$_2$) monolayers, demonstrating strong light matter interactions and locked spin and valley degrees of freedom. In heterobilayers composed of overlapping monolayers of two different MX$_2$, an interlayer exciton can form, with the hole localised in one layer and the electron in the other. These interlayer excitons are long-lived, field-tunable, and can be trapped by moir'e patterns formed at small twist angles between the layers. Here we demonstrate that emission from radiative recombination of interlayer excitons can be observed by cathodoluminescence from a WSe$_2$/MoSe$_2$ heterobilayer encapsulated in hexagonal boron nitride. The higher spatial resolution of cathodoluminescence, compared to photoluminescence, allows detailed analysis of sample heterogeneity at the 100s of nm lengthscales over which twist angles tend to vary in dry-transfer fabricated heterostructures.

Yohannes Getahun et al 2024 Nanotechnology

The present work demonstrates synthesis and elucidation of Fe nanoparticles surrounded by citrate matrix prepared at various temperatures and concentrations of the metal, capping agent and reducing agent at standard conditions. We study the effect of reactants ratio and reaction temperature on magnetization of nanoparticles and their crystal structure. We found out that at optimal metal concentrations, magnetic saturation increases with increase in concentrations of capping and reducing agents but decreases as the temperature of the reaction increases. Synthesis conditions are tailored revealing nucleation of particles with average size ranging from 24 to 105 nm and spherical shape. Ultra-high saturation magnetization of 241 and 228 emu/g obtained for samples prepared at 0oC and metal precursor concentration of 27.8 mole/L which attributed to the formation of small magnetic domain size. Hence, we demonstrate that the concentration of the reducing agent and temperature of the reaction environment are crucial for monitoring the tunability of magnetization in Fe-CIT nanoparticle systems.

Brandon N Julien et al 2024 Nanotechnology 35 445501

Interactions between carbon nanotubes (CNTs) and fluid flows are central to the operation of several emerging nanotechnologies. In this paper, we explore the fluid-structure interaction of CNT micropillars in wall-bounded shear flows, relevant to recently developed microscale wall shear stress sensors. We monitor the deformation of CNT micropillars in channel flow as the flow rate and wall shear stress are gradually varied. We quantify how the micropillars bend at low wall shear stress, and then will commonly tilt abruptly from their base above a threshold wall shear stress, which is attributed to the lower density of the micropillars in this region. Some micropillars are observed to flutter rapidly between a vertical and horizontal position around this threshold wall shear stress, before settling to a tilted position as wall shear stress increases further. Tilted micropillars are found to kink sharply near their base, similar to the observed buckling near the base of CNT micropillars in compression. Upon reducing the flow rate, micropillars are found to fully recover from a near horizontal position to a near vertical position, even with repeated on–off cycling. At sufficiently high wall shear stress, the micropillars were found to detach at the catalyst particle-substrate interface. The mechanical response of CNT micropillars in airflow revealed by this study provides a basis for future development efforts and the accurate simulation of CNT micropillar wall shear stress sensors.

Chien-Hao Huang and Sheng-Yuan Chu 2024 Nanotechnology 35 445601

Cesium lead bromide (CsPbBr 3 ) perovskite nanocrystals are becoming a popular alternative to chalcogenide quantum dots because of their bright green fluorescence and high color purity. However, owing to the poor stability caused by their highly ionic nature and the dynamic binding of long-chain capping ligands, their practical applications are limited. Although (3-aminopropyl)triethoxysilane (APTES) is a frequently used insulating material for wrapping CsPbBr 3 nanocrystals, it often causes surface etching. To address this issue, we introduced oleic acid into the anti-solvent toluene to inhibit the etching effect of APTES using a modified room-temperature ligand-assisted reprecipitation process. We utilized in situ time-dependent photoluminescence measurements to study the formation kinetics of CsPbBr 3 nanocrystals and determine the optimal ligands ratio. This innovative approach enables precise control over CsPbBr 3 @SiO 2 nanoparticles synthesis, yielding uniformly shaped nanocrystals with a silica shell, a consistent size around 10.17 ± 1.6 nm, and enhanced photoluminescence quantum yields ranging from 90% and 100%. The photoluminescence lifetimes of our CsPbBr 3 @SiO 2 nanoparticles were significantly prolonged owing to a reduction in non-radiative recombination. This boosts their stability in thermal and polar solvent environments, making them superior candidates for use in photonic devices.

Bowen Zhang et al 2024 Nanotechnology

High-quality patterning determines the properties of patterned emerging two-dimensional (2D) conjugated polymers which is essential for potential applications in future electronic nanodevices. However, the suitable patterning method for 2D polymers is yet concluded because it's still challenging to gain comprehensive understanding of their damage mechanisms by visualizing the structural modification during patterning process. Here, the damage mechanisms during patterning of 2D polymers, induced by various patterning methods, are unveiled based on a systematic study of structural damage and edge morphology on an imine-based 2D polymer (polyimine). Patterning using focused electron beam, focused ion beam (FIB) and mechanical carving is evaluated. Focused electron beam successively introduces sputtering effect, knock-on displacement damage and massive radiolysis effect as increasing the electron dose from 9.46 × 107 e-/nm2 to 1.14 × 1010 e-/nm2. The successful pattering is enabled by knock-on damage while impeded by carbon contamination when beyond a critical sample thickness. FIB creates current-dependent edge morphologies and extensive damage from the ion implantation caused by the tail of unfocused beam. A precisely controlled tip can tear the polyimine film through grain boundaries and in hence create the patterning edge with suitable edge roughness for certain application senarios when the beam damage is avoided. Taking structural damage and the resulting quantitative edge roughness into consideration, this study provides a detailed instruction on the proper patterning techniques for 2D crystalline polymers and paves the way for tailored intrinsic properties and device fabrication using these novel materials.

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• 1990-present Nanotechnology doi: 10.1088/issn.0957-4484 Online ISSN: 1361-6528 Print ISSN: 0957-4484

• Open access
• Published: 19 September 2018

Nano based drug delivery systems: recent developments and future prospects

• Jayanta Kumar Patra   ORCID: orcid.org/0000-0003-4118-4355 1 ,
• Gitishree Das 1 ,
• Leonardo Fernandes Fraceto 2 , 3 ,
• Estefania Vangelie Ramos Campos 2 , 3 ,
• Maria del Pilar Rodriguez-Torres   ORCID: orcid.org/0000-0001-9107-247X 4 ,
• Laura Susana Acosta-Torres   ORCID: orcid.org/0000-0002-5959-9113 4 ,
• Luis Armando Diaz-Torres   ORCID: orcid.org/0000-0002-1281-9916 5 ,
• Renato Grillo 6 ,
• Mallappa Kumara Swamy 7 ,
• Shivesh Sharma 8 ,
• Solomon Habtemariam 9 &
• Han-Seung Shin 10  

Journal of Nanobiotechnology volume  16 , Article number:  71 ( 2018 ) Cite this article

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Nanomedicine and nano delivery systems are a relatively new but rapidly developing science where materials in the nanoscale range are employed to serve as means of diagnostic tools or to deliver therapeutic agents to specific targeted sites in a controlled manner. Nanotechnology offers multiple benefits in treating chronic human diseases by site-specific, and target-oriented delivery of precise medicines. Recently, there are a number of outstanding applications of the nanomedicine (chemotherapeutic agents, biological agents, immunotherapeutic agents etc.) in the treatment of various diseases. The current review, presents an updated summary of recent advances in the field of nanomedicines and nano based drug delivery systems through comprehensive scrutiny of the discovery and application of nanomaterials in improving both the efficacy of novel and old drugs (e.g., natural products) and selective diagnosis through disease marker molecules. The opportunities and challenges of nanomedicines in drug delivery from synthetic/natural sources to their clinical applications are also discussed. In addition, we have included information regarding the trends and perspectives in nanomedicine area.

Since ancient times, humans have widely used plant-based natural products as medicines against various diseases. Modern medicines are mainly derived from herbs on the basis of traditional knowledge and practices. Nearly, 25% of the major pharmaceutical compounds and their derivatives available today are obtained from natural resources [ 1 , 2 ]. Natural compounds with different molecular backgrounds present a basis for the discovery of novel drugs. A recent trend in the natural product-based drug discovery has been the interest in designing synthetically amenable lead molecules, which mimic their counterpart’s chemistry [ 3 ]. Natural products exhibit remarkable characteristics such as extraordinary chemical diversity, chemical and biological properties with macromolecular specificity and less toxicity. These make them favorable leads in the discovery of novel drugs [ 4 ]. Further, computational studies have helped envisage molecular interactions of drugs and develop next-generation drug inventions such as target-based drug discovery and drug delivery.

Despite several advantages, pharmaceutical companies are hesitant to invest more in natural product-based drug discovery and drug delivery systems [ 5 ] and instead explore the available chemical compounds libraries to discover novel drugs. However, natural compounds are now being screened for treating several major diseases, including cancer, diabetes, cardiovascular, inflammatory, and microbial diseases. This is mainly because natural drugs possess unique advantages, such as lower toxicity and side effects, low-price, and good therapeutic potential. However, concerns associated with the biocompatibility, and toxicity of natural compounds presents a greater challenge of using them as medicine. Consequently, many natural compounds are not clearing the clinical trial phases because of these problems [ 6 , 7 , 8 ]. The use of large sized materials in drug delivery poses major challenges, including in vivo instability, poor bioavailability, and poor solubility, poor absorption in the body, issues with target-specific delivery, and tonic effectiveness, and probable adverse effects of drugs. Therefore, using new drug delivery systems for targeting drugs to specific body parts could be an option that might solve these critical issues [ 9 , 10 ]. Hence, nanotechnology plays a significant role in advanced medicine/drug formulations, targeting arena and their controlled drug release and delivery with immense success.

Nanotechnology is shown to bridge the barrier of biological and physical sciences by applying nanostructures and nanophases at various fields of science [ 11 ]; specially in nanomedicine and nano based drug delivery systems, where such particles are of major interest [ 12 , 13 ]. Nanomaterials can be well-defined as a material with sizes ranged between 1 and 100 nm, which influences the frontiers of nanomedicine starting from biosensors, microfluidics, drug delivery, and microarray tests to tissue engineering [ 14 , 15 , 16 ]. Nanotechnology employs curative agents at the nanoscale level to develop nanomedicines. The field of biomedicine comprising nanobiotechnology, drug delivery, biosensors, and tissue engineering has been powered by nanoparticles [ 17 ]. As nanoparticles comprise materials designed at the atomic or molecular level, they are usually small sized nanospheres [ 18 ]. Hence, they can move more freely in the human body as compared to bigger materials. Nanoscale sized particles exhibit unique structural, chemical, mechanical, magnetic, electrical, and biological properties. Nanomedicines have become well appreciated in recent times due to the fact that nanostructures could be utilized as delivery agents by encapsulating drugs or attaching therapeutic drugs and deliver them to target tissues more precisely with a controlled release [ 10 , 19 ]. Nanomedicine, is an emerging field implementing the use of knowledge and techniques of nanoscience in medical biology and disease prevention and remediation. It implicates the utilization of nanodimensional materials including nanorobots, nanosensors for diagnosis, delivery, and sensory purposes, and actuate materials in live cells (Fig.  1 ). For example, a nanoparticle-based method has been developed which combined both the treatment and imaging modalities of cancer diagnosis [ 20 ]. The very first generation of nanoparticle-based therapy included lipid systems like liposomes and micelles, which are now FDA-approved [ 21 ]. These liposomes and micelles can contain inorganic nanoparticles like gold or magnetic nanoparticles [ 22 ]. These properties let to an increase in the use of inorganic nanoparticles with an emphasis on drug delivery, imaging and therapeutics functions. In addition, nanostructures reportedly aid in preventing drugs from being tarnished in the gastrointestinal region and help the delivery of sparingly water-soluble drugs to their target location. Nanodrugs show higher oral bioavailability because they exhibit typical uptake mechanisms of absorptive endocytosis.

Application and goals of nanomedicine in different sphere of biomedical research

Nanostructures stay in the blood circulatory system for a prolonged period and enable the release of amalgamated drugs as per the specified dose. Thus, they cause fewer plasma fluctuations with reduced adverse effects [ 23 ]. Being nanosized, these structures penetrate in the tissue system, facilitate easy uptake of the drug by cells, permit an efficient drug delivery, and ensure action at the targeted location. The uptake of nanostructures by cells is much higher than that of large particles with size ranging between 1 and 10 µm [ 17 , 24 ]. Hence, they directly interact to treat the diseased cells with improved efficiency and reduced or negligible side effects.

At all stages of clinical practices, nanoparticles have been found to be useful in acquiring information owing to their use in numerous novel assays to treat and diagnose diseases. The main benefits of these nanoparticles are associated with their surface properties; as various proteins can be affixed to the surface. For instance, gold nanoparticles are used as biomarkers and tumor labels for various biomolecule detection procedural assays.

Regarding the use of nanomaterials in drug delivery, the selection of the nanoparticle is based on the physicochemical features of drugs. The combined use of nanoscience along with bioactive natural compounds is very attractive, and growing very rapidly in recent times. It presents several advantages when it comes to the delivery of natural products for treating cancer and many other diseases. Natural compounds have been comprehensively studied in curing diseases owing to their various characteristic activities, such as inducing tumor-suppressing autophagy and acting as antimicrobial agents. Autophagy has been observed in curcumin and caffeine [ 25 ], whereas antimicrobial effects have been shown by cinnamaldehyde, carvacrol, curcumin and eugenol [ 26 , 27 ]. The enrichment of their properties, such as bioavailability, targeting and controlled release were made by incorporating nanoparticles. For instance, thymoquinone, a bioactive compound in Nigella sativa , is studied after its encapsulation in lipid nanocarrier. After encapsulation, it showed sixfold increase in bioavailability in comparison to free thymoquinone and thus protects the gastrointestinal stuffs [ 28 ]. It also increased the pharmacokinetic characteristics of the natural product resulting in better therapeutic effects.

Metallic, organic, inorganic and polymeric nanostructures, including dendrimers, micelles, and liposomes are frequently considered in designing the target-specific drug delivery systems. In particular, those drugs having poor solubility with less absorption ability are tagged with these nanoparticles [ 17 , 29 ]. However, the efficacy of these nanostructures as drug delivery vehicles varies depending on the size, shape, and other inherent biophysical/chemical characteristics. For instance, polymeric nanomaterials with diameters ranging from 10 to 1000 nm, exhibit characteristics ideal for an efficient delivery vehicle [ 7 ]. Because of their high biocompatibility and biodegradability properties, various synthetic polymers such as polyvinyl alcohol, poly- l -lactic acid, polyethylene glycol, and poly(lactic- co -glycolic acid), and natural polymers, such as alginate and chitosan, are extensively used in the nanofabrication of nanoparticles [ 8 , 30 , 31 , 32 ]. Polymeric nanoparticles can be categorized into nanospheres and nanocapsules both of which are excellent drug delivery systems. Likewise, compact lipid nanostructures and phospholipids including liposomes and micelles are very useful in targeted drug delivery.

The use of ideal nano-drug delivery system is decided primarily based on the biophysical and biochemical properties of the targeted drugs being selected for the treatment [ 8 ]. However, problems such as toxicity exhibited by nanoparticles cannot be ignored when considering the use of nanomedicine. More recently, nanoparticles have mostly been used in combination with natural products to lower the toxicity issues. The green chemistry route of designing nanoparticles loaded with drugs is widely encouraged as it minimises the hazardous constituents in the biosynthetic process. Thus, using green nanoparticles for drug delivery can lessen the side-effects of the medications [ 19 ]. Moreover, adjustments in nanostructures size, shape, hydrophobicity, and surface changes can further enhance the bioactivity of these nanomaterials.

Thus, nanotechnology offers multiple benefits in treating chronic human diseases by site-specific, and target-oriented delivery of medicines. However, inadequate knowledge about nanostructures toxicity is a major worry and undoubtedly warrants further research to improve the efficacy with higher safety to enable safer practical implementation of these medicines. Therefore, cautiously designing these nanoparticles could be helpful in tackling the problems associated with their use. Considering the above facts, this review aims to report different nano based drug delivery systems, significant applications of natural compound-based nanomedicines, and bioavailability, targeting sites, and controlled release of nano-drugs, as well as other challenges associated with nanomaterials in medicines.

Nano based drug delivery systems

Recently, there has been enormous developments in the field of delivery systems to provide therapeutic agents or natural based active compounds to its target location for treatment of various aliments [ 33 , 34 ]. There are a number of drug delivery systems successfully employed in the recent times, however there are still certain challenges that need to be addresses and an advanced technology need to be developed for successful delivery of drugs to its target sites. Hence the nano based drug delivery systems are currently been studied that will facilitate the advanced system of drug delivery.

Fundamentals of nanotechnology based techniques in designing of drug

Nanomedicine is the branch of medicine that utilizes the science of nanotechnology in the preclusion and cure of various diseases using the nanoscale materials, such as biocompatible nanoparticles [ 35 ] and nanorobots [ 36 ], for various applications including, diagnosis [ 37 ], delivery [ 38 ], sensory [ 39 ], or actuation purposes in a living organism [ 40 ]. Drugs with very low solubility possess various biopharmaceutical delivery issues including limited bio accessibility after intake through mouth, less diffusion capacity into the outer membrane, require more quantity for intravenous intake and unwanted after-effects preceding traditional formulated vaccination process. However all these limitations could be overcome by the application of nanotechnology approaches in the drug delivery mechanism.

Drug designing at the nanoscale has been studied extensively and is by far, the most advanced technology in the area of nanoparticle applications because of its potential advantages such as the possibility to modify properties like solubility, drug release profiles, diffusivity, bioavailability and immunogenicity. This, can consequently lead to the improvement and development of convenient administration routes, lower toxicity, fewer side effects, improved biodistribution and extended drug life cycle [ 17 ]. The engineered drug delivery systems are either targeted to a particular location or are intended for the controlled release of therapeutic agents at a particular site. Their formation involves self-assembly where in well-defined structures or patterns spontaneously are formed from building blocks [ 41 ]. Additionally they need to overcome barriers like opsonization/sequestration by the mononuclear phagocyte system [ 42 ].

There are two ways through which nanostructures deliver drugs: passive and self-delivery. In the former, drugs are incorporated in the inner cavity of the structure mainly via the hydrophobic effect. When the nanostructure materials are targeted to a particular sites, the intended amount of the drug is released because of the low content of the drugs which is encapsulated in a hydrophobic environment [ 41 ]. Conversely, in the latter, the drugs intended for release are directly conjugated to the carrier nanostructure material for easy delivery. In this approach, the timing of release is crucial as the drug will not reach the target site and it dissociates from the carrier very quickly, and conversely, its bioactivity and efficacy will be decreased if it is released from its nanocarrier system at the right time [ 41 ]. Targeting of drugs is another significant aspect that uses nanomaterials or nanoformulations as the drug delivery systems and, is classified into active and passive. In active targeting, moieties, such as antibodies and peptides are coupled with drug delivery system to anchor them to the receptor structures expressed at the target site. In passive targeting, the prepared drug carrier complex circulates through the bloodstream and is driven to the target site by affinity or binding influenced by properties like pH, temperature, molecular site and shape. The main targets in the body are the receptors on cell membranes, lipid components of the cell membrane and antigens or proteins on the cell surfaces [ 43 ]. Currently, most nanotechnology-mediated drug delivery system are targeted towards the cancer disease and its cure.

Biopolymeric nanoparticles in diagnosis, detection and imaging

The integration of therapy and diagnosis is defined as theranostic and is being extensively utilized for cancer treatment [ 44 , 45 ]. Theranostic nanoparticles can help diagnose the disease, report the location, identify the stage of the disease, and provide information about the treatment response. In addition, such nanoparticles can carry a therapeutic agent for the tumor, which can provide the necessary concentrations of the therapeutic agent via molecular and/or external stimuli [ 44 , 45 ]. Chitosan is a biopolymer which possesses distinctive properties with biocompatibility and presence of functional groups [ 45 , 46 , 47 ]. It is used in the encapsulation or coating of various types of nanoparticles, thus producing different particles with multiple functions for their potential uses in the detection and diagnosis of different types of diseases [ 45 , 47 ].

Lee et al. [ 48 ] encapsulated oleic acid-coated FeO nanoparticles in oleic acid-conjugated chitosan (oleyl-chitosan) to examine the accretion of these nanoparticles in tumor cells through the penetrability and holding (EPR) consequence under the in vivo state for analytical uses by the near-infrared and magnetic resonance imaging (MRI) mechanisms. By the in vivo evaluations, both techniques showed noticeable signal strength and improvement in the tumor tissues through a higher EPR consequence after the injection of cyanine-5-attached oleyl-chitosan nanoparticles intravenously (Cyanine 5).

Yang et al. [ 49 ] prepared highly effective nanoparticles for revealing colorectal cancer (CC) cells via a light-mediated mechanism; these cells are visible owing to the physical conjugation of alginate with folic acid-modified chitosan leading to the formation of nanoparticles with enhanced 5-aminolevulinic (5-ALA) release in the cell lysosome. The results displayed that the engineered nanoparticles were voluntarily endocytosed by the CC cells by the folate receptor-based endocytosis process. Subsequently, the charged 5-ALA was dispersed into the lysosome which was triggered by less desirability strength between the 5-ALA and chitosan through deprotonated alginate that gave rise to the gathering of protoporphyrin IX (PpIX) for photodynamic detection within the cells. As per this research, chitosan-based nanoparticles in combination with alginate and folic acid are tremendous vectors for the definite delivery of 5-ALA to the CC cells to enable endoscopic fluorescent detection. Cathepsin B (CB) is strongly associated with the metastatic process and is available in surplus in the pericellular areas where this process occurs; thus, CB is important for the detection of metastasis. Ryu et al. [ 50 ] designed a CB-sensitive nanoprobe (CB-CNP) comprising a self-satisfied CB-CNP with a fluorogenic peptide attached to the tumor-targeting glycol chitosan nanoparticles (CNPs) on its surface. The designed nanoprobe is a sphere with a diameter of 280 nm, with spherical structure and its fluorescence capacity was completely extinguished under the biological condition. The evaluation of the usability of CB-sensitive nanoprobe in three rat metastatic models demonstrated the potential of these nonoprobes in discriminating metastatic cells from healthy ones through non-invasive imaging. Hyaluronic acid (HA) is another biopolymeric material. This is a biocompatible, negatively charged glycosaminoglycan, and is one of the main constituents of the extracellular matrix [ 51 , 52 ]. HA can bind to the CD44 receptor, which is mostly over articulated in various cancerous cells, through the receptor-linker interaction. Thus, HA-modified nanoparticles are intriguing for their use in the detection and cure of cancer [ 53 , 54 , 55 ]. Wang et al. [ 56 ], coated the surface of iron oxide nanoparticles (IONP) with dopamine-modified HA. These nanoparticles have a hydrophilic exterior and a hydrophobic interior where the chemotherapeutic homocamptothecin is encapsulated [ 56 ]. The biopotential of this process was investigated in both laboratory and in the live cells. Increased uptake of nanoparticles by tumor cells was observed by MRI when an external magnetic field was employed [ 56 ]. After the intravenous administration of the nano-vehicle in 3 mg/kg (relative to the free drug) rats, a large tumor ablation was observed and after treatment, the tumors almost disappeared [ 56 ].

Choi et al. [ 53 ] also synthesized nanoparticles of hyaluronic acid with different diameters by changing the degree of hydrophobic replacement of HA. The nanoparticles were systemically administered in the mice with tumor, and then, its effect was studied. This same research group developed a versatile thermostatic system using poly (ethylene glycol) conjugated hyaluronic acid (P-HA-NPs) nanoparticles for the early detection of colon cancer and targeted therapy. To assess the effectiveness of the nanoparticles, they were first attached to the near-infrared fluorescent dye (Cy 5.5) by chemical conjugation, and then, the irinotecan anticancer drug (IRT) was encapsulated within these systems. The therapeutic potential of P-HA-NP was then investigated in different systems of the mice colon cancer. Through the intravenous injection of the fluorescent dye attached nanoparticles (Cy 5.5-P-HA-NPs), minute and initial-stage tumors as well as liver-embedded colon tumors were efficiently pictured using an NIRF imaging method. Due to their extraordinary capability to target tumors, drug-containing nanoparticles (IRT-P-HA-NP) showed markedly decreased tumor development with decreased systemic harmfulness. In addition, healing effects could be examined concurrently with Cy 5.5-P-HA-NPs [ 57 ].

Another option that can be used is alginate, which is a natural polymer derived from the brown seaweed and has been expansively scrutinized for its potential uses in the biomedical field because of its several favorable characteristics, such as low cost of manufacture, harmonious nature, less harmfulness, and easy gelling in response to the addition of divalent cations [ 58 , 59 ]. Baghbani et al. [ 60 ] prepared perfluorohexane (PFH) nanodroplets stabilized with alginate to drive doxorubicin and then evaluated their sensitivity to ultrasound and imaging as well as their therapeutic properties. Further found that the ultrasound-facilitated treatment with PFH nanodroplets loaded with doxorubicin exhibited promising positive responses in the breast cancer rat models. The efficacy was characterized by the deterioration of the tumor [ 60 ]. In another study, Podgorna et al. [ 61 ] prepared gadolinium (GdNG) containing nanogels for hydrophilic drug loading and to enable screening by MRI. The gadolinium alginate nanogels had an average diameter of 110 nm with stability duration of 60 days. Because of their paramagnetic behavior, the gadolinium mixtures are normally used as positive contrast agents (T1) in the MRI images. Gadolinium nanogels significantly reduce the relaxation time (T1) compared to controls. Therefore, alginate nanogels act as contrast-enhancing agents and can be assumed as an appropriate material for pharmacological application.

Also, the polymeric material dextran is a neutral polymer and is assumed as the first notable example of microbial exopolysaccharides used in medical applications. A remarkable advantage of using dextran is that it is well-tolerated, non-toxic, and biodegradable in humans, with no reactions in the body [ 62 ]. Photodynamic therapy is a site-specific cancer cure with less damage to non-cancerous cells. Ding et al. [ 63 ] prepared a nanoparticulate multifunctional composite system by encapsulating Fe 3 O 4 nanoparticles in dextran nanoparticles conjugated to redox-responsive chlorine 6 (C6) for near infrared (NIR) and magnetic resonance (MR) imaging. The nanoparticles exhibited an “off/on” behavior of the redox cellular response of the fluorescence signal, thus resulting in accurate imaging of the tumor. In addition, excellent in vitro and in vivo magnetic targeting ability was observed, contributing to the efficacy of enhanced photodynamic therapy. Hong et al. [ 64 ] prepared theranostic nanoparticles or glioma cells of C6 mice. These particles comprised of gadolinium oxide nanoparticles coated with folic acid-conjugated dextran (FA) or paclitaxel (PTX). The bioprotective effects of dextran coating and the chemotherapeutic effect of PTX on the C6 glioma cells were evaluated by the MTT assay. The synthesized nanoparticles have been shown to enter C6 tumor cells by receptor-mediated endocytosis and provide enhanced contrast (MR) concentration-dependent activity due to the paramagnetic property of the gadolinium nanoparticle. Multifunctional nanoparticles were more effective in reducing cell viability than uncoated gadolinium nanoparticles. Therefore, FA and PTX conjugated nanoparticles can be used as theranostic agents with paramagnetic and chemotherapeutic properties.

Drug designing and drug delivery process and mechanism

With the progression of nanomedicine and, due to the advancement of drug discovery/design and drug delivery systems, numerous therapeutic procedures have been proposed and traditional clinical diagnostic methods have been studied, to increase the drug specificity and diagnostic accuracy. For instance, new routes of drug administration are being explored, and there is focus on ensuring their targeted action in specific regions, thus reducing their toxicity and increasing their bioavailability in the organism [ 65 ].

In this context, drug designing has been a promising feature that characterizes the discovery of novel lead drugs based on the knowledge of a biological target. The advancements in computer sciences, and the progression of experimental procedures for the categorization and purification of proteins, peptides, and biological targets are essential for the growth and development of this sector [ 66 , 67 ]. In addition, several studies and reviews have been found in this area; they focus on the rational design of different molecules and show the importance of studying different mechanisms of drug release [ 68 ]. Moreover, natural products can provide feasible and interesting solutions to address the drug design challenges, and can serve as an inspiration for drug discovery with desired physicochemical properties [ 3 , 69 , 70 ].

Also, the drug delivery systems have been gaining importance in the last few years. Such systems can be easily developed and are capable of promoting the modified release of the active ingredients in the body. For example, Chen et al. [ 70 ] described an interesting review using nanocarriers for imaging and sensory applications and discussed the, therapy effect of these systems. In addition, Pelaz et al. [ 71 ] provided an up-to-date overview of several applications of nanocarriers to nanomedicine and discussed new opportunities and challenges for this sector.

Interestingly, each of these drug delivery systems has its own chemical, physical and morphological characteristics, and may have affinity for different drugs polarities through chemical interactions (e.g., covalent bonds and hydrogen bonds) or physical interactions (e.g., electrostatic and van der Waals interactions). As an example, Mattos et al. [ 72 ] demonstrated that, the release profile of neem bark extract-grafted biogenic silica nanoparticles (chemical interactions) was lower than neem bark extract-loaded biogenic silica nanoparticles. Hence, all these factors influence the interaction of nanocarriers with biological systems [ 73 ], as well as the release kinetics of the active ingredient in the organism [ 68 ]. In addition, Sethi et al. [ 74 ] designed a crosslinkable lipid shell (CLS) containing docetaxel and wortmannin as the prototypical drugs used for controlling the drug discharge kinetics; then, they studied, its discharge profile, which was found to be affected in both in vivo and in vitro conditions. Apart from this, other parameters, such as the composition of the nanocarriers (e.g., organic, inorganic, and hybrid materials) and the form in which drugs are associated with them (such as core–shell system or matrix system) are also fundamental for understanding their drug delivery profile [ 75 , 76 ]. Taken together, several studies regarding release mechanisms of drugs in nanocarriers have been conducted. Diffusion, solvent, chemical reaction, and stimuli-controlled release are a few mechanisms that can represent the release of drugs in nanocarriers as shown in Fig.  2 [ 77 , 78 ]. Kamaly et al. [ 79 ] provided a widespread review of controlled-release systems with a focus on studies related to controlling drug release from polymeric nanocarriers.

Mechanisms for controlled release of drugs using different types of nanocarriers

Although there are several nanocarriers with different drug release profiles, strategies are currently being formulated to improve the specificity of the nanostructures to target regions of the organism [ 80 ], and to reduce the immunogenicity through their coating or chemical functionalization with several substances, such as polymers [ 81 ], natural polysaccharides [ 82 , 83 ], antibodies [ 84 ], cell-membrane [ 85 ], and tunable surfactants [ 86 ], peptides [ 87 ], etc. In some cases where drugs do not display binding and affinity with a specific target or do not cross certain barriers (e.g. blood–brain barrier or the blood–cerebrospinal fluid barrier) [ 88 ], these ligand-modified nanocarriers have been used to pass through the cell membrane and allow a programmed drug delivery in a particular environment. For example, hyaluronic acid (a polysaccharide found in the extracellular matrix) has been used as a ligand-appended in several nanocarriers, showing promising results to boost antitumor action against the melanoma stem-like cells [ 89 ], breast cancer cells [ 90 ], pulmonary adenocarcinoma cells [ 91 ], as well as to facilitate intravitreal drug delivery for retinal gene therapy [ 83 ] and to reduce the immunogenicity of the formed protein corona [ 82 ]. However, the construction of the ligand-appended drug delivery systems is labor-intensive, and several targeting designs must be performed previously, taking into account the physiological variables of blood flow, disease status, and tissue architecture [ 92 ]. Moreover, few studies have been performed to evaluate the interaction of the ligand-appended in nanocarriers with cell membranes, and also their uptake mechanism is still unclear. Furthermore, has been known that the uptake of the nanoparticles by the cells occurs via phagocytic or non-phagocytic pathways (e.x. clathrin-mediated endocytosis, caveolae-mediated endocytosis, and others) [ 93 , 94 ], meanwhile due some particular physicochemical characteristics of each delivery systems have been difficult to standardize the mechanism of action/interaction of these systems in the cells. For example, Salatin and Khosroushahi [ 95 ], in a review highlighted the main endocytosis mechanisms responsible for the cellular uptake of polysaccharide nanoparticles containing active compounds.

On the other hand, stimuli-responsive nanocarriers have shown the ability to control the release profile of drugs (as a triggered release) using external factors such as ultrasound [ 96 ], heat [ 97 , 98 , 99 ], magnetism [ 100 , 101 ], light [ 102 ], pH [ 103 ], and ionic strength [ 104 ], which can improve the targeting and allow greater dosage control (Fig.  2 ). For example, superparamagnetic iron oxide nanoparticles are associated with polymeric nanocarriers [ 105 ] or lipids [ 106 ] to initially stimulate a controlled release system by the application of external magnetic field. In addition, Ulbrich et al. [ 107 ] revised recent achievements of drug delivery systems, in particular, on the basis of polymeric and magnetic nanoparticles, and also addressed the effect of covalently or noncovalently attached drugs for cancer cure [ 107 ]. Moreover, Au/Fe 3 O 4 @polymer nanoparticles have also been synthesized for the use in NIR-triggered chemo-photothermal therapy [ 108 ]. Therefore, hybrid nanocarriers are currently among the most promising tools for nanomedicine as they present a mixture of properties of different systems in a single system, thus ensuring materials with enhanced performance for both therapeutic and diagnostic applications (i.e., theranostic systems). Despite this, little is known about the real mechanisms of action and toxicity of drug delivery systems, which open opportunity for new studies. In addition, studies focusing on the synthesis of nanocarriers based on environmentally safe chemical reactions by implementing plant extracts and microorganisms have increased [ 10 ].

Nanoparticles used in drug delivery system

Biopolymeric nanoparticles.

There are numerous biopolymeric materials that are utilized in the drug delivery systems. These materials and their properties are discussed below.

Chitosan exhibits muco-adhesive properties and can be used to act in the tight epithelial junctions. Thus, chitosan-based nanomaterials are widely used for continued drug release systems for various types of epithelia, including buccal [ 109 ], intestinal [ 110 ], nasal [ 111 ], eye [ 112 ] and pulmonary [ 113 ]. Silva et al. [ 114 ] prepared and evaluated the efficacy of a 0.75% w/w isotonic solution of hydroxypropyl methylcellulose (HPMC) containing chitosan/sodium tripolyphosphate/hyaluronic acid nanoparticles to deliver the antibiotic ceftazidime to the eye. The rheological synergism parameter was calculated by calculating the viscosity of the nanoparticles in contact with mucin in different mass proportions. A minimum viscosity was observed when chitosan nanoparticles were placed in contact with mucin. However, the nanoparticles presented mucoadhesion which resulted in good interaction with the ocular mucosa and prolonged release of the antibiotic, and therefore, the nanoparticles can enhance the life span of the drug in the eyes. The nanoparticles did not show cytotoxicity for two cell lines tested (ARPE-19 and HEK 239T). The nanoparticles were also able to preserve the antibacterial activity, thus making them a promising formulations for the administration of ocular drugs with improved mucoadhesive properties.

Pistone et al. [ 115 ] prepared nanoparticles of chitosan, alginate and pectin as potential candidates for the administration of drugs into the oral cavity. The biocompatibility of the formulations was estimated based on the solubility of the nanoparticles in a salivary environment and its cytotoxicity potential was estimated in an oral cell line. Alginate nanoparticles were the most unwavering in the artificial saliva for at least 2 h, whereas pectin and especially chitosan nanoparticles were unstable. However, the chitosan nanoparticles were the most cyto-competitive, whereas alginate and pectin nanoparticles showed cytotoxicity under all tested conditions (concentration and time). The presence of Zn 2+ (cross-linking agent) may be the cause of the observed cytotoxicity. Each formulation presented advantage and limitations for release into the oral cavity, thus necessitating their further refinement.

In addition, Liu et al. [ 116 ] prepared nanoparticles of carboxymethyl chitosan for the release of intra-nasal carbamazepine (CBZ) to bypass the blood–brain barrier membrane, thus increasing the amount of the medication in the brain and refining the treatment efficacy, thereby reducing the systemic drug exposure. The nanoparticles had a mean diameter of 218.76 ± 2.41 nm, encapsulation efficiency of 80% and drug loading of 35%. Concentrations of CBZ remained higher (P < 0.05) in the brain than the plasma over 240 min.

In another example, Jain and Jain [ 117 ] investigated the discharge profile of 5-fluorouracil (5-FU) from hyaluronic acid-coated chitosan nanoparticles into the gut, via oral administration. Release assays in conditions mimicking the transit from the stomach to the colon indicated the release profile of 5-FU which was protected against discharge in the stomach and small intestine. Also, the high local concentration of drugs would be able to increase the exposure time and thus, enhance the capacity for antitumor efficacy and decrease the systemic toxicity in the treatment of colon cancer.

Another biopolymeric material that has been used as a drug delivery is alginate. This biopolymer presents final carboxyl groups, being classified as anionic mucoadhesive polymer and presents greater mucoadhesive strength when compared with cationic and neutral polymers [ 59 , 118 ]. Patil and Devarajan [ 119 ] developed insulin-containing alginate nanoparticles with nicotinamide as a permeation agent in order to lower the serum glucose levels and raise serum insulin levels in diabetic rats. Nanoparticles administered sublingually (5 IU/kg) in the presence of nicotinamide showed high availability pharmacology (> 100%) and bioavailability (> 80%). The fact that NPs are promising carriers of insulin via the sublingual route have been proved in case of the streptozotocin-induced diabetic mouse model by achieving a pharmacological high potential of 20.2% and bio-availability of 24.1% compared to the subcutaneous injection at 1 IU/kg [ 119 ].

Also, Haque et al. [ 120 ] prepared alginate nanoparticles to release venlafaxine (VLF) via intranasal for treatment of depression. The higher blood/brain ratios of the VLF concentration to the alginate nanoparticles administered intra-nasally when compared to the intranasal VLF and VLF solution intravenously indicated the superiority of the nano-formulation in directly transporting the VLF to the brain. In this way, these nanoparticles are promising for the treatment of depression. In another example, Román et al. [ 121 ] prepared alginate microcapsules containing epidermal growth factor bound on its exterior part to target the non-small cell lung cancer cells. Cisplatin (carcinogen drug) was also loaded in the nanoparticles. The addition of EGF significantly increased specificity of carrier systems and presented kinetics of cell death (H460-lung cancer strain) faster than the free drug.

In addition, Garrait et al. [ 122 ] prepared nanoparticles of chitosan containing Amaranth red (AR) and subsequently microencapsulated these nanoparticles in alginate microparticles and studied the release kinetics of this new system in simulated gastric and intestinal fluids. The microparticles had a mean diameter of 285 μm with a homogeneous distribution; it was observed that there was a release of less than 5% of the AR contained in the systems in the gastric pH conditions, whereas the discharge was fast and comprehensive in the intestinal pH conditions. Thus, the carrier showed promise to protect molecules for intestinal release after oral administration.

Costa et al. [ 123 ] prepared chitosan-coated alginate nanoparticles to enhance the permeation of daptomycin into the ocular epithelium aiming for an antibacterial effect. In vitro permeability was assessed using ocular epithelial cell culture models. The antimicrobial activity of nanoencapsulated daptomycin showed potential over the pathogens engaged in bacterial endophthalmitis. Also, the ocular permeability studies demonstrated that with 4 h of treatment from 9 to 12% in total of daptomycin encapsulated in chitosan/alginate nanoparticles, these were able to cross the HCE and ARPE-19 cells. These results indicated that with this system an increasing in the drug retention in the ocular epithelium has occurred.

Xanthan gum

Xanthan gum (XG) is a high molecular weight heteropolysaccharide produced by Xanthomonas campestris . It is a polyanionic polysaccharide and has good bioadhesive properties. Because it is considered non-toxic and non-irritating, xanthan gum is widely used as a pharmaceutical excipient [ 124 ].

Laffleur and Michalek [ 125 ] have prepared a carrier composed of xanthan gum thiolated with l -cysteine to release tannin in the buccal mucosa to treat sialorrhea. Thiolation of xanthan gum resulted in increased adhesion on the buccal mucosa when compared to native xanthan gum. In addition, xanthan gum thiolate has a higher uptake of saliva whereas tannic acid ad-string and dry the oral mucosa. In this way, this system would be an efficient way of reducing the salivary flow of patients with sialorrhea. Angiogenesis is an important feature in regeneration of soft tissues.

Huang et al. [ 126 ] prepared injectable hydrogels composed of aldehyde-modified xanthan and carboxymethyl-modified chitosan containing potent angiogenic factor (antivascular endothelial growth factor, VEGF) to improve abdominal wall reconstruction. The hydrogel presented release properties mainly in tissues like digestive tract and open wounds. The hydrogel containing VEGF was able to accelerate the angiogenesis process and rebuild the abdominal wall. Menzel et al. [ 127 ] studied a new excipient aiming the use as nasal release system. Xanthan gum was used as a major polymer in which the-((2-amino-2-carboxyethyl) disulfanyl) nicotinic acid (Cys-MNA) was coupled. Characteristics, such as amount of the associated binder, mucoadhesive properties and stability against degradation, were analyzed in the resulting conjugate. Each gram of polymer was ligated with 252.52 ± 20.54 μmol of the binder. The muco-adhesion of the grafted polymer was 1.7 fold greater than that of thiolated xanthan and 2.5 fold greater than, that of native xanthan. In addition, the frequency of ciliary beating of nasal epithelial cells was poorly affected and was reversible only upon the removal of the polymer from the mucosa.

Cellulose and its derivatives are extensively utilized in the drug delivery systems basically for modification of the solubility and gelation of the drugs that resulted in the control of the release profile of the same [ 128 ]. Elseoud et al. [ 129 ] investigated the utilization of cellulose nanocrystals and chitosan nanoparticles for the oral releasing of repaglinide (an anti-hyperglycemic—RPG). The chitosan nanoparticles showed a mean size distribution of 197 nm while the hybrid nanoparticles of chitosan and cellulose nanocrystals containing RPG. Chitosan hybrid nanoparticles and oxidized cellulose nanocrystals containing RPG had a mean diameter of 251–310 nm. The presence of the hydrogen bonds between the cellulose nanocrystals and the drug, resulted in sustained release of the same, and subsequently the nanoparticles made with oxidized cellulose nanocrystals presented lower release when compared to the nanoparticles produced with native cellulose nanocrystals.

Agarwal et al. [ 130 ] have developed a drug targeting mechanism which is based on the conjugation of calcium alginate beads with carboxymethylcellulose (CMC) loaded 5-fluoroacyl (5-FU) and is targeted to the colon. The beads with lower CMC proportions presented greater swelling and muco-adhesiveness in the simulated colonic environment. With existence of colonic enzymes there was a 90% release of 5-FU encapsulated in the beads. Hansen et al. [ 131 ] investigated four cellulose derivatives, including, meteylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and cationic hydroxyethyl cellulose for application in drug release into the nasal mucosa. The association of these cellulose derivatives with an additional excipient, was also evaluated. The drug model employed in this process was acyclovir. The viability of the polymers as excipients for nasal release applications was also scrutinized for its ciliary beat frequency (CBF) and its infusion through the tissue system of the nostril cavity. An increase in thermally induced viscosity was observed when the cellulose derivatives were mixed with polymer graft copolymer. Further an increased permeation of acyclovir into the nasal mucosa was detected when it was combined with cationic hydroxyethylcellulose. None of the cellulose derivatives caused negative effects on tissues and cells of the nasal mucosa, as assessed by CBF.

They were discovered by Alec Bangham in 1960. Liposomes are used in the pharmaceutical and cosmetics industry for the transportation of diverse molecules and are among the most studied carrier system for drug delivery. Liposomes are an engrained formulation strategy to improve the drug delivery. They are vesicles of spherical form composed of phospholipids and steroids usually in the 50–450 nm size range [ 132 ]. These are considered as a better drug delivery vehicles since their membrane structure is analogous to the cell membranes and because they facilitate incorporation of drugs in them [ 132 ]. It has also been proved that they make therapeutic compounds stable, improve their biodistribution, can be used with hydrophilic and hydrophobic drugs and are also biocompatible and biodegradable. Liposomes are divided into four types: (1) conventional type liposomes: these consists of a lipid bilayer which can make either anionic, cationic, or neutral cholesterol and phospholipids, which surrounds an aqueous core material. In this case, both the lipid bilayer and the aqueous space can be filled with hydrophobic or hydrophilic materials, respectively. (2) PEGylated types: polyethylene glycol (PEG) is incorporated to the surface of liposome to achieve steric equilibrium, (3) ligand-targeted type: ligands like antibodies, carbohydrates and peptides, are linked to the surface of the liposome or to the end of previously attached PEG chains and (4) theranostic liposome type: it is an amalgamation kind of the previous three types of liposomes and generally consists of a nanoparticle along with a targeting, imaging and a therapeutic element [ 133 ].

The typical synthesis procedure for liposomes are as follows, thin layer hydration, mechanical agitation, solvent evaporation, solvent injection and the surfactant solubilization [ 134 ]. One aspect to point out on liposomes is that the drugs that are trapped within them are not bioavailable until they are released. Therefore, their accumulation in particular sites is very important to increase drug bioavailability within the therapeutic window at the right rates and times. Drug loading in liposomes is attained by active (drug encapsulated after liposome formation) and passive (drug encapsulated during liposome formation) approaches [ 135 ]. Hydrophilic drugs such as ampicillin and, 5-fluoro-deoxyuridine are typically confined in the aqueous core of the liposome and thus, their encapsulation does not depend on any modification in the drug/lipid ratio. However, the hydrophobic ones such as Amphotericin B, Indomethacin were found in the acyl hydrocarbon chain of the liposome and thus their engulfing are subjected to the characteristics of the acyl chain [ 136 ]. Among the passive loading approaches the mechanical and the solvent dispersion method as well as the detergent removal method can be mentioned [ 135 ].

There are obstacles with the use of liposomes for drug delivery purposes in the form of the RES (reticuloendothelial system), opsonization and immunogenicity although there are factors like enhanced permeability and EPR (retention effect) that can be utilized in order to boost the drug delivery efficiency of the liposomes [ 133 , 135 ]. Once liposomes get into the body, they run into opsonins and high density lipoproteins (HDLs) and low density lipoproteins (LDLs) while circulating in the bloodstream by themselves. Opsonins (immunoglobulins and fibronectin, for example) assist RES on recognizing and eliminating liposomes. HDLs and LDLs have interactions with liposomes and decrease their stability. Liposomes tends to gather more in the sites like the liver and the spleen, this is an advantage because then a high concentration of liposomes can help treat pathogenic diseases, although in the case of cancers this can lead to a delay in the removal of lipophilic anticancer drugs. This is the reason why as mentioned at the beginning, different types of liposomes have been developed, in this case PEGylated ones. Dimov et al. [ 137 ] reported an incessant procedure of flow system for the synthesis, functionalization and cleansing of liposomes. This research consists of vesicles under 300 nm in a lab-on-chip that are useful and potential candidates for cost-intensive drugs or protein encapsulation development [ 137 ]. This is very important because costs of production also determine whether or not a specific drug can be commercialized. Liposome-based systems have now been permitted by the FDA [ 133 , 135 , 138 , 139 , 140 ].

Polymeric micelles

Polymeric micelles are nanostructures made of amphiphilic block copolymers that gather by itself to form a core shell structure in the aqueous solution. The hydrophobic core can be loaded with hydrophobic drugs (e.g. camptothecin, docetaxel, paclitaxel), at the same time the hydrophilic shell makes the whole system soluble in water and stabilizes the core. Polymeric micelles are under 100 nm in size and normally have a narrow distribution to avoid fast renal excretion, thus permitting their accumulation in tumor tissues through the EPR effect. In addition, their polymeric shell restrains nonspecific interactions with biological components. These nanostructures have a strong prospective for hydrophobic drug delivery since their interior core structure permits the assimilation of these kind of drugs resulting in enhancement of stability and bioavailability [ 141 , 142 ].

Polymeric micelles are synthesized by two approaches: (1) convenient solvent-based direct dissolution of polymer followed by dialysis process or (2) precipitation of one block by adding a solvent [ 142 , 143 ]. The factors like, hydrophobic chain size in the amphiphilic molecule, amphiphiles concentration, solvent system and temperature, affects the micelle formation [ 144 ]. The micelle assembly creation starts when minimum concentration known as the critical micelle concentration (CMC) is reached by the amphiphilic molecules [ 143 ]. At lower concentrations, the amphiphilic molecules are indeed small and occur independently [ 143 ]. Drugs are loaded within polymeric micelles by three common methodologies such as direct dissolution process, solvent evaporation process, and the dialysis process. As of the direct dissolution process, the copolymer and the drugs combine with each other by themselves in the water medium and forms a drug loaded with the micelles. While in the solvent evaporation process, the copolymer and the intended drug is dissolved using a volatile organic solvent and finally, in case of the dialysis process, both the drug in solution and the copolymer in the organic solvent are combined in the dialysis bag and then dialyzed with the formation of the micelle [ 145 ].

The targeting of the drugs using different polymeric micelles as established by various mechanism of action including the boosted penetrability and the holding effect stimuli; complexing of a definite aiming ligand molecule to the surface of the micelle; or by combination of the monoclonal antibodies to the micelle corona [ 146 ]. Polymeric micelles are reported to be applicable for both drug delivery against cancer [ 143 ] and also for ocular drug delivery [ 147 ] as shown in Fig.  3 in which a polymeric micelle is used for reaching the posterior ocular tissues [ 147 ]. In the work by Li et al. [ 148 ], dasatinib was encapsulated within nanoparticles prepared from micellation of PEG-b-PC, to treat proliferative vitreoretinopathy (PVR), their size was 55 nm with a narrow distribution and they turned out to be noncytotoxic to ARPE-19 cells. This micellar formulation ominously repressed the cell proliferation, attachment and relocation in comparison to the free drugs [ 148 ]. The polymeric micelles is habitually get into the rear eye tissues through the transcleral pathway after relevant applications (Fig.  3 ; [ 147 ]).

(the figure is reproduced from Mandal et al. [ 147 ] with required copyright permission)

Polymeric micelles used for reaching the posterior ocular tissues via the transcleral pathway after topical application

Dendrimers are highly bifurcated, monodisperse, well-defined and three-dimensional structures. They are globular-shaped and their surface is functionalized easily in a controlled way, which makes these structures excellent candidates as drug delivery agents [ 149 , 150 , 151 ]. Dendrimers can be synthesized by means of two approaches: The first one is the different route in which the dendrimer starts formation from its core and then it is extended outwards and the second is the convergent one, starts from the outside of the dendrimer [ 152 ]. Dendrimers are grouped into several kinds according to their functionalization moieties: PAMAM, PPI, liquid crystalline, core–shell, chiral, peptide, glycodendrimers and PAMAMOS, being PAMAM, the most studied for oral drug delivery because it is water soluble and it can pass through the epithelial tissue boosting their transfer via the paracellular pathway [ 153 ]. Dendrimers are limited in their clinical applications because of the presence of amine groups. These groups are positively charged or cationic which makes them toxic, hence dendrimers are usually modified in order to reduce this toxicity issue or to eliminate it. Drug loading in dendrimers is performed via the following mechanisms: Simple encapsulation, electrostatic interaction and covalent conjugation [ 154 ].

Drug is basically delivered by the dendrimers following two different paths, a) by the in vivo degradation of drug dendrimer’s covalent bonding on the basis of availability of suitable enzymes or favorable environment that could cleave the bonds and b) by discharge of the drug due to changes in the physical environment like pH, temperature etc., [ 154 ]. Dendrimers have been developed for transdermal, oral, ocular, pulmonary and in targeted drug delivery [ 155 ].

Jain et al. [ 156 ] have described the folate attached poly- l -lysine dendrimers (doxorubicin hydrochloride) as a capable cancer prevention drug carrier model for pH dependent drug discharge, target specificity, antiangiogenic and anticancer prospective, it was shown that doxorubicin-folate conjugated poly- l -lysine dendrimers increased the concentration of doxorubicin in the tumor by 121.5-fold after 24 h compared with free doxorubicin. Similarly, (Kaur et al. [ 157 ] developed folate-conjugated polypropylene imine dendrimers (FA-PPI) as a methotrexate (MTX) nanocarrier, for pH-sensitive drug release, selective targeting to cancer cells, and anticancer treatment. The in vitro studies on them showed sustained release, increased cell uptake and low cytotoxicity on MCF-7 cell lines [ 157 ]. Further, it has to be pointed out that the developed formulations, methotrexate (MTX)-loaded and folic acid-conjugated 5.0G PPI (MTX-FA-PPI), were selectively taken up by the tumor cells in comparison with the free drug, methotrexate (MTX).

Inorganic nanoparticles

Inorganic nanoparticles include silver, gold, iron oxide and silica nanoparticles are included. Studies focused on them are not as many as there are on other nanoparticle types discussed in this section although they show some potential applications. However, only few of the nanoparticles have been accepted for its clinical use, whereas the majority of them are still in the clinical trial stage. Metal nanoparticles, silver and gold, have particular properties like SPR (surface plasmon resonance), that liposomes, dendrimers, micelles do not possess. They showed several advantages such as good biocompatibility and versatility when it comes to surface functionalization.

Studies on their drug delivery-related activity have not been able to clear out whether the particulate or ionized form is actually related to their toxicity, and even though two mechanisms have been proposed, namely paracellular transport and transcytosis, there is not enough information about their in vivo transport and uptake mechanism [ 158 ]. Drugs can be conjugated to gold nanoparticles (AuNPs) surfaces via ionic or covalent bonding and physical absorption and they can deliver them and control their release through biological stimuli or light activation [ 159 ]. Silver nanoparticles exhibited antimicrobial activity, but as for drug delivery, very few studies have been carried out, for example, Prusty and Swain [ 160 ] synthesized an inter-linked and spongy polyacrylamide/dextran nano-hydrogels hybrid system with covalently attached silver nanoparticles for the release of ornidazole which turned out to have an in vitro release of 98.5% [ 160 ]. Similarly in another study, the iron oxide nanoparticles were synthesized using laser pyrolysis method and were covered with Violamycine B1, and antracyclinic antibiotics and tested against the MCF-7 cells for its cytotoxicity and the anti-proliferation properties along with its comparison with the commercially available iron oxide nanoparticles [ 161 ].

Nanocrystals

Nanocrystals are pure solid drug particles within 1000 nm range. These are 100% drug without any carriers molecule attached to it and are usually stabilized by using a polymeric steric stabilizers or surfactants. A nanocrystals suspension in a marginal liquid medium is normally alleviated by addition of a surfactant agent known as nano-suspension. In this case, the dispersing medium are mostly water or any aqueous or non-aqueous media including liquid polyethylene glycol and oils [ 162 , 163 ]. Nanocrystals possesses specific characters that permit them to overcome difficulties like increase saturation solubility, increased dissolution velocity and increased glueyness to surface/cell membranes. The process by which nanocrystals are synthesized are divided into top-down and bottom-up approaches. The top-down approach includes, sono-crystallization, precipitation, high gravity controlled precipitation technology, multi-inlet vortex mixing techniques and limited impinging liquid jet precipitation technique [ 162 ]. However, use of an organic solvent and its removal at the end makes this process quite expensive. The bottom-up approach involves, grinding procedures along with homogenization at higher pressure [ 162 ]. Among all of the methods, milling, high pressure homogenization, and precipitation are the most used methods for the production of nanocrystals. The mechanisms by which nanocrystals support the absorption of a drug to the system includes, enhancement of solubility, suspension rate and capacity to hold intestinal wall firmly [ 162 ]. Ni et al. [ 164 ] embedded cinaciguat nanocrystals in chitosan microparticles for pulmonary drug delivery of the hydrophobic drug. The nanoparticles were contrived for continuous release of the drug taking advantage of the swelling and muco-adhesive potential of the polymer. They found that inhalation efficacy might be conceded under the disease conditions, so more studies are needed to prove that this system has more potential [ 164 ].

Metallic nanoparticles

In recent years, the interest of using metallic nanoparticles has been growing in different medical applications, such as bioimaging, biosensors, target/sustained drug delivery, hyperthermia and photoablation therapy [ 35 , 165 ]. In addition, the modification and functionalization of these nanoparticles with specific functional groups allow them to bind to antibodies, drugs and other ligands, become these making these systems more promising in biomedical applications [ 166 ]. Although the most extensively studied, metallic nanoparticles are gold, silver, iron and copper, a crescent interest has been exploited regarding other kinds of metallic nanoparticles, such as, zinc oxide, titanium oxide, platinum, selenium, gadolinium, palladium, cerium dioxide among others [ 35 , 165 , 166 ].

Quantum dots

Quantum dots (QDs) are known as semiconductor nanocrystals with diameter range from 2 to 10 nm and their optical properties, such as absorbance and photoluminescence are size-dependent [ 167 ]. The QDs has gained great attention in the field of nanomedicine, since, unlike conventional organic dyes, the QDs presents emission in the near-infrared region (< 650 nm), a very desirable characteristic in the field of biomedical images, due to the low absorption by the tissues and reduction in the light scattering [ 167 , 168 ]. In addition, QDs with different sizes and/or compositions can be excited by the same light source resulting in separate emission colors over a wide spectral range [ 169 , 170 ]. In this sense, QDs are very appealing for multiplex imaging. In the medicine field QDs has been extensively studied as targeted drug delivery, sensors and bioimaging. A large number of studies regarding the applications of QDs as contrast agents for in vivo imaging is currently available in literature [ 168 , 171 , 172 , 173 ]. Han et al. [ 172 ] developed a novel fluorophore for intravital cytometric imaging based on QDs-antibodies conjugates coated with norbornene-displaying polyimidazole ligands. This fluorophore was used to label bone marrow cells in vivo. The authors found that the fluorophore was able to diffuse in the entire bone marrow and label rare populations of cells, such as hematopoietic stem and progenitor cells [ 172 ]. Shi et al. [ 171 ] developed a multifunctional biocompatible graphene oxide quantum dot covered with luminescent magnetic nanoplatform for recognize/diagnostic of a specific liver cancer tumor cells (glypican-3-expressing Hep G2). According to the authors the attachment of an anti-GPC3-antibody to the nanoplataform results in selective separation of Hep G2 hepatocellular carcinoma cells from infected blood samples [ 171 ]. QDs could also bring benefits in the sustained and/or controlled release of therapeutic molecules. Regarding the controlled release, this behavior can be achieved via external stimulation by light, heat, radio frequency or magnetic fields [ 170 , 174 , 175 ]. Olerile et al. [ 176 ] have developed a theranostic system based on co-loaded of QDs and anti-cancer drug in nanostructured lipid carriers as a parenteral multifunctional system. The nanoparticles were spherical with higher encapsulation efficiency of paclitaxel (80.7 ± 2.11%) and tumor growth inhibition rate of 77.85%. The authors also found that the system was able to specifically target and detect H22 tumor cells [ 176 ]. Cai et al. [ 177 ] have synthesized pH responsive quantum dots based on ZnO quantum dots decorated with PEG and hyaluronic acid for become stable in physiological conditions and for targeting specific cells with HA-receptor CD44, respectively. This nanocarrier was also evaluated for doxorubicin (DOX) sustained release. The nanocarrier was stable in physiological pH and DOX was loaded in the carrier by forming complex with Zn 2+ ions or conjugated to PEG. The DOX was released only in acidic intracellular conditions of tumor cells due to the disruption of ZnO QDs. The authors found that the anticancer activity was enhanced by the combination of DOX and ZnO QDs [ 177 ].

Protein and polysaccharides nanoparticles

Polysaccharides and proteins are collectively called as natural biopolymers and are extracted from biological sources such as plants, animals, microorganisms and marine sources [ 178 , 179 ]. Protein-based nanoparticles are generally decomposable, metabolizable, and are easy to functionalize for its attachment to specific drugs and other targeting ligands. They are normally produced by using two different systems, (a) from water-soluble proteins like bovine and human serum albumin and (b) from insoluble ones like zein and gliadin [ 180 ]. The usual methods to synthesize them are coacervation/desolvation, emulsion/solvent extraction, complex coacervation and electrospraying. The protein based nanoparticles are chemically altered in order to combine targeting ligands that identify exact cells and tissues to promote and augment their targeting mechanism [ 180 ]. Similarly, the polysaccharides are composed of sugar units (monosaccharides) linked through O-glycosidic bonds. The composition of these monomers as well as their biological source are able to confer to these polysaccharides, a series of specific physical–chemical properties [ 126 , 179 , 181 ]. One of the main drawback of the use of polysaccharides in the nanomedicine field is its degradation (oxidation) characteristics at high temperatures (above their melting point) which are often required in industrial processes. Besides, most of the polysaccharides are soluble in water, which limits their application in some fields of nanomedicine, such as tissue engineering [ 182 , 183 ]. However, techniques such as crosslinking of the polymer chains have been employed in order to guarantee stability of the polysaccharide chains, guaranteeing them stability in aqueous environments [ 182 , 183 ]. In Fig.  4 , examples of some polysaccharides used in nanomedicine obtained from different sources are summarized. The success of these biopolymers in nanomedicine and drug delivery is due to their versatility and specified properties such as since they can originate from soft gels, flexible fibers and hard shapes, so they can be porous or non-porous; they have great similarity with components of the extracellular matrix, which may be able to avoid immunological reactions [ 179 , 184 ].

Different sources of natural biopolymers to be used in nanomedicine applications. Natural biopolymers could be obtained from higher plants, animals, microorganisms and algae

There is not much literature related to these kind of nanoparticles, however, since they are generated from biocompatible compounds they are excellent candidates for their further development as drug delivery systems. Yu et al. [ 185 ] synthesized Bovine serum albumin and tested its attachment and/or infiltration property through the opening of the cochlea and middle ear of guinea pigs. The nanoparticles considered as the drug transporters were tested for their loading capacity and release behaviors that could provide better bio-suitability, drug loading capacity, and well-ordered discharge mechanism [ 185 ].

Natural product-based nanotechnology and drug delivery

As per the World Health Organization (WHO) report, in developing countries, the basic health needs of approximately 80% of the population are met and/or complemented by traditional medicine [ 186 ]. Currently, the scientific community is focusing on the studies related to the bioactive compounds, its chemical composition and pharmacological potential of various plant species, to produce innovative active ingredients that present relatively minor side effects than existing molecules [ 5 , 187 ]. Plants are documented as a huge sources of natural compounds of medicinal importance since long time and still it holds ample of resources for the discovery of new and highly effective drugs. However, the discovery of active compounds through natural sources is associated with several issues because they originate from living beings whose metabolite composition changes in the presence of stress. In this sense, the pharmaceutical industries have chosen to combine their efforts in the development of synthetic compounds [ 187 , 188 , 189 ]. Nevertheless, the number of synthetic molecules that are actually marketed are going on decreasing day by day and thus research on the natural product based active compounds are again coming to the limelight in spite of its hurdles [ 189 , 190 ]. Most of the natural compounds of economic importance with medicinal potential that are already being marketed have been discovered in higher plants [ 187 , 191 ]. Several drugs that also possess natural therapeutic agents in their composition are already available commercially; their applications and names are as follows: malaria treatment (Artemotil ® derived from Artemisia annua L., a traditional Chinese medicine plant), Alzheimer’s disease treatment (Reminyl ® , an acetylcholinesterase inhibitor isolated from the Galanthus woronowii Losinsk), cancer treatment (Paclitaxel ® and its analogues derived from the Taxus brevifolia plant; vinblastine and vincristine extracted from Catharanthus roseus ; camptothecin and its analogs derived from Camptotheca acuminata Decne), liver disease treatment (silymarin from Silybum marianum ) [ 187 ].

The composition and activity of many natural compounds have already been studied and established. The alkaloids, flavonoids, tannins, terpenes, saponins, steroids, phenolic compounds, among others, are the bioactive molecules found in plants. However in most of the cases, these compounds have low absorption capacity due to the absence of the ability to cross the lipid membranes because of its high molecular sizes, and thus resulting in reduced bioavailability and efficacy [ 192 ]. These molecules also exhibit high systemic clearance, necessitating repeated applications and/or high doses, making the drug less effective for therapeutic use [ 189 ]. The scientific development of nanotechnology can revolutionize the development of formulations based on natural products, bringing tools capable of solving the problems mentioned above that limits the application of these compounds in large scale in the nanomedicine [ 7 , 189 ]. Utilization of nanotechnology techniques in the medical field has been extensively studied in the last few years [ 193 , 194 ]. Hence these can overcome these barriers and allow different compounds and mixtures to be used in the preparation of the same formulation. In addition, they can change the properties and behavior of a compound within the biological system [ 7 , 189 ]. Besides, bringing benefits to the compound relative to the solubility and stability of the compounds, release systems direct the compound to the specific site, increase bioavailability and extend compound action, and combine molecules with varying degrees of hydrophilicity/lipophilicity [ 7 ]. Also, there is evidence that the association of release systems with natural compounds may help to delay the development of drug resistance and therefore plays an important role in order to find new possibilities for the treatment of several diseases that have low response to treatment conventional approaches to modern medicine [ 7 , 189 ].

The natural product based materials are of two categories, (1) which are targeted to specific location and released in the specific sites to treat a number of diseases [ 43 , 195 ] and (2) which are mostly utilized in the synthesis process [ 196 ]. Most of the research is intended for treatment against the cancer disease, since it is the foremost reason of death worldwide nowadays [ 197 , 198 ]. In case of the cancer disease, different organs of the body are affected, and therefore the need for the development of an alternative medicine to target the cancerous cells is the utmost priority among the modern researchers, however, a number of applications of nanomedicine to other ailments is also being worked on [ 199 , 200 ]. These delivery systems are categorized in terms of their surface charge, particle size, size dispersion, shape, stability, encapsulation potential and biological action which are further utilized as per their requirements [ 33 ]. Some examples of biological compounds obtained from higher plants and their uses in the nanomedicine field are described in Fig.  5 . Pharmaceutical industries have continuously sought the development and application of new technologies for the advancement and design of modern drugs, as well as the enhancement of existing ones [ 71 , 201 ]. In this sense, the accelerated development of nanotechnology has driven the design of new formulations through different approaches, such as, driving the drug to the site of action (nanopharmaceutics); image and diagnosis (nanodiagnostic), medical implants (nanobiomaterials) and the combination diagnosis and treatment of diseases (nanotheranostics) [ 71 , 202 , 203 ].

Examples of natural compounds extracted from higher plants used in nanomedicine aiming different approaches. Some of these extracts are already being marketed, others are in clinical trials and others are being extensively studied by the scientific community

Currently, many of the nanomedicines under development, are modified release systems for active ingredients (AI) that are already employed in the treatment of patients [ 203 , 204 ]. For this type of approach, it is evaluated whether the sustained release of these AIs modifies the pharmacokinetic profile and biodistribution. In this context, it can be ascertained that the nano-formulation offers advantages over the existing formulation if the AI is directed towards the target tissue shows increased uptake/absorption by the cells and lower toxicity profile for the organism [ 205 , 206 ]. This section is focused on berberine, curcumin, ellagic acid, resveratrol, curcumin and quercetin [ 8 ]. Some other compounds mentioned are doxorubicin, paclitaxel and vancomycin that also come from natural products.

Nanoparticles have been synthesized using natural products. For example, metallic, metal oxide and sulfides nanoparticles have been reported to be synthesized using various microorganisms including bacteria, fungi, algae, yeast and so on [ 207 ] or plant extracts [ 208 ]. For the first approach, the microorganism that aids the synthesis procedure is prepared in the adequate growth medium and then mixed with a metal precursor in solution and left for incubation to form the nanoparticles either intracellularly or extracellularly [ 209 , 210 , 211 ]. As for the second approach, the plant extract is prepared and mixed afterwards with the metal precursor in solution and incubated further at room temperature or boiling temperature for a definite time or exposed to light as an external stimulus to initiate the synthesis of nanoparticles [ 212 ].

Presently, these natural product based materials are considered as the key ingredients in the preparation and processing of new nano-formulations because they have interesting characteristics, such as being biodegradable, biocompatible, availability, being renewable and presenting low toxicity [ 178 , 179 , 213 ]. In addition to the aforementioned properties, biomaterials are, for the most part, capable of undergoing chemical modifications, guaranteeing them unique and desirable properties for is potential uses in the field of nanomedicine [ 45 , 214 ]. Gold, silver, cadmium sulfide and titanium dioxide of different morphological characteristics have been synthesized using a number of bacteria namely Escherichia coli , Pseudomonas aeruginosa , Bacillus subtilis and Klebsiella pneumoniae [ 211 ]. These nanoparticles, especially the silver nanoparticles have been abundantly studied in vitro for their antibacterial, antifungal, and cytotoxicity potential due to their higher potential among all metal nanoparticles [ 215 , 216 ]. In the event of microorganism mediated nanoparticle synthesis, maximum research is focused on the way that microorganisms reduce metal precursors and generate the nanoparticles. For instance, Rahimi et al. [ 217 ] synthesized silver nanoparticles using Candida albicans and studied their antibacterial activity against two pathogenic bacteria namely Staphylococcus aureus and E. coli. Similarly, Ali et al. [ 218 ] synthesized silver nanoparticles with the Artemisia absinthium aqueous extract and their antimicrobial activity was assessed versus Phytophthora parasitica and Phytophthora capsici [ 218 ]. Further, Malapermal et al. [ 219 ] used Ocimum basilicum and Ocimum sanctum extracts to synthesize nanoparticles and studied its antimicrobial potential against E. coli , Salmonella spp., S. aureus , and P. aeruginosa along with the antidiabetic potential. Likewise, Sankar et al. [ 220 ] also tested the effect of silver nanoparticles for both antibacterial and anticancer potential against human lung cancer cell line. Besides the use of microorganism, our group has synthesized silver, gold and iron oxide nanoparticles using various food waste materials such as extracts of Zea mays leaves [ 221 , 222 ], onion peel extract [ 223 ], silky hairs of Zea mays [ 224 ], outer peel of fruit of Cucumis melo and Prunus persica [ 225 ], outer peel of Prunus persica [ 226 ] and the rind extract of watermelon [ 227 ], etc. and have tested their potential antibacterial effects against various foodborne pathogenic bacteria, anticandidal activity against a number of pathogenic Candida spp., for their potential antioxidant activity and proteasome inhibitory effects.

For drug delivery purposes, the most commonly studied nanocarriers are crystal nanoparticles, liposomes, micelles, polymeric nanoparticles, solid lipid nanoparticles, superparamagnetic iron oxide nanoparticles and dendrimers [ 228 , 229 , 230 ]. All of these nanocarriers are formulated for natural product based drug delivery. For applications in cancer treatment, Gupta et al. [ 231 ] synthesized chitosan based nanoparticles loaded with Paclitaxel (Taxol) derived from Taxus brevifolia , and utilized them for treatment of different kinds of cancer. The authors concluded that the nanoparticle loaded drug exhibited better activity with sustained release, high cell uptake and reduced hemolytic toxicity compared with pure Paclitaxel [ 231 ]. Berberine is an alkaloid from the barberry plant. Chang et al. [ 232 ] created a heparin/berberine conjugate to increase the suppressive Helicobacter pylori growth and at the same time to reduce cytotoxic effects in infected cells [ 232 ] which is depicted in Fig.  6 .

(the figure is reproduced from Chang et al. [ 232 ] with required copyright permission)

a Structure of berberine/heparin based nanoparticles and berberine/heparin/chitosan nanoparticles. b TEM images of the berberine/heparin nanoparticles and berberine/heparin/chitosan nanoparticles

Aldawsari and Hosny [ 233 ] synthesized ellagic acid-SLNs to encapsulate Vancomycin (a glycopeptide antibiotic produced in the cultures of Amycolatopsis orientalis ). Further, its in vivo tests were performed on rabbits and the results indicated that the ellagic acid prevented the formation of free oxygen radicals and their clearance radicals, thus preventing damages and promoting repair [ 233 ]. Quercetin is a polyphenol that belongs to the flavonoid group, it can be found in citrus fruits and vegetables and it has antioxidant properties. In a study by Dian et al. [ 234 ], polymeric micelles was used to deliver quercetin and the results showed that such micelles could provide continuous release for up to 10 days in vitro, with continuous plasma level and boosted complete accessibility of the drug under in vivo condition [ 234 ].

Daunorubicin is a natural product derived from a number of different wild type strains of Streptomyces , doxorubicin (DOX) is a hydrolated version of it used in chemotherapy [ 213 ]. Spillmann et al. [ 235 ] developed a multifunctional liquid crystal nanoparticle system for intracellular fluorescent imaging and for the delivery of doxorubicin in which the nanoparticles were functionalized with transferrin. Cellular uptake and sustained released were attained within endocytic vesicles in HEK 293T/17 cells. Perylene was used as a chromophore to track the particles and to encapsulate agents aimed for intracellular delivery [ 235 ]. Purama et al. [ 236 ] extracted dextran from two sucrose based lactic acid bacteria namely Streptococcus mutans and Leuconostoc mesenteroides . Agarwal et al. [ 237 ] formulated a dextran-based dendrimer formulation and evaluated its drug discharge capacity and haemolytic activity under in vitro condition. They concluded that the dendritic structure selectively enters the highly permeable portion of the affected cells without disturbing the healthy tissues thereby making more convenient for its application in the biomedical field [ 237 ]. Folate- functionalized superparamagnetic iron oxide nanoparticles developed previously for liver cancer cure are also been used for the delivery of Doxil (a form of doxorubicin which was the first FDA-approved nano-drug in 1995) [ 238 ]. The in vivo studies in rabbits and rats showed a two- and fourfold decrease compared with Doxil alone while folate aided and enhanced specific targeting [ 239 ]. Liposomes are the nanostructures that have been studied the most, and they have been used in several formulations for the delivery of natural products like resveratrol [ 240 ]. Curcumin, a polyphenolic compound obtained from turmeric, have been reported to be utilized in the cure of cancers including the breast, bone, cervices, liver, lung, and prostate [ 241 ]. Liposomal curcumin formulations have been developed for the treatment of cancer [ 242 , 243 ]. Cheng et al. [ 244 ] encapsulated curcumin in liposomes by different methods and compared the outcomes resulting that the one dependent on pH yielded stable products with good encapsulation efficiency and bio-accessibility with potential applications in cancer treatment [ 244 ].

Over all, it can be said that the sustained release systems of naturally occurring therapeutic compounds present themselves as a key tools for improving the biological activity of these compounds as well as minimizing their limitations by providing new alternatives for the cure of chronic and terminal diseases [ 8 , 245 ]. According to BBC Research, the global market for plant-derived pharmaceuticals will increase from $29.4 billion in 2017 to about $39.6 billion in 2022 with a compound annual growth rate (CAGR) of 6.15% in this period (BCC-RESEARCH). Some of nanostructure-based materials covered in this section have already been approved by the FDA. Bobo et al. [ 255 ] has provided the information on nanotechnology-based products already approved by the FDA (Table  1 ).

Regulation and reality: products now on the market

In the current medical nanotechnology scenario, there are 51 products based on this technology [ 204 , 246 , 247 , 248 ] which are currently being applied in clinical practice (Table  2 ). Notably, such nanomedicines are primarily developed for drugs, which have low aqueous solubility and high toxicity, and these nanoformulations are often capable of reducing the toxicity while increasing the pharmacokinetic properties of the drug in question.

According to a recent review by Caster et al. [ 249 ], although few nanomedicines have been regulated by the FDA there are many initiatives that are currently in progress in terms of clinical trials suggesting many nanotechnology-based new drugs will soon be able to reach the market. Among these nanomaterials that are in phase of study, 18 are directed to chemotherapeutics; 15 are intended for antimicrobial agents; 28 are for different medical applications and psychological diseases, autoimmune conditions and many others and 30 are aimed at nucleic acid based therapies [ 249 ]. The list of nanomedicine approved by FDA classified by type of carrier/material used in preparation of the formulation is shown in Table  2 .

Nanotechnology has dynamically developed in recent years, and all countries, whether developed or not, are increasing their investments in research and development in this field. However, researchers who work with practical applications of the nano-drugs deal with high levels of uncertainties, such as a framing a clear definition of these products; characterization of these nanomaterials in relation to safety and toxicity; and the lack of effective regulation. Although the list of approved nanomedicine is quite extensive, the insufficiency of specific regulatory guidelines for the development and characterization of these nanomaterials end up hampering its clinical potential [ 250 ]. The structure/function relationships of various nanomaterials, as well as their characteristics, composition and surface coating, interacts with the biological systems. In addition, it is important to evaluate the possibility of aggregate and agglomerate formation when these nanomedicines are introduced into biological systems, since they do not reflect the properties of the individual particle; this may generate different results and/or unexpected toxic effects depending on the nano-formulation [ 250 ].

The lack of standard protocols for nanomedicines characterization at physico-chemical and physiological/biological levels has often limited the efforts of many researchers to determine the toxic potential of nano-drugs in the early stages of testing, and that resulted in the failures in late-phase clinical trials. To simplify and/or shorten the approval process for nano based medicines/drugs, drug delivery system etc., a closer cooperation among regulatory agencies is warranted [ 204 , 251 ].

As a strategy for the lack of regulation of nanomedicines and nano drug delivery system; the safety assessment and the toxicity and compatibility of these are performed based on the regulations used by the FDA for conventional drugs. After gaining the status of a new research drug (Investigational New Drug, IND) by the FDA, nanomedicines, nano-drug delivery systems begin the clinical trials phase to investigate their safety and efficacy in humans. These clinical trials are divided into three phases: phase 1 (mainly assesses safety); phase 2 (mainly evaluates efficacy) and phase 3 (safety, efficacy and dosage are evaluated). After approval in these three phases the IND can be filed by the FDA to request endorsement of the new nanomedicine or nano drug delivery systems. However, this approach to nanomedicine regulation has been extensively questioned [ 204 , 246 , 252 ].

Due to the rapid development of nanotechnology as well as its potential use of nanomedicine, a reformed and more integrated regulatory approach is urgently required. In this regard, country governments must come together to develop new protocols that must be specific and sufficiently rigorous to address any safety concerns, thus ensuring the release of safe and beneficial nanomedicine for patients [ 204 , 252 , 253 ].

Future of nanomedicine and drug delivery system

The science of nanomedicine is currently among the most fascinating areas of research. A lot of research in this field in the last two decades has already led to the filling of 1500 patents and completion of several dozens of clinical trials [ 254 ]. As outlined in the various sections above, cancer appears to be the best example of diseases where both its diagnosis and therapy have benefited from nonmedical technologies. By using various types of nanoparticles for the delivery of the accurate amount of drug to the affected cells such as the cancer/tumour cells, without disturbing the physiology of the normal cells, the application of nanomedicine and nano-drug delivery system is certainly the trend that will remain to be the future arena of research and development for decades to come.

The examples of nanoparticles showed in this communications are not uniform in their size, with some truly measuring in nanometers while others are measured in sub-micrometers (over 100 nm). More research on materials with more consistent uniformity and drug loading and release capacity would be the further area of research. Considerable amount of progress in the use of metals-based nanoparticles for diagnostic purposes has also been addressed in this review. The application of these metals including gold and silver both in diagnosis and therapy is an area of research that could potentially lead to wider application of nanomedicines in the future. One major enthusiasm in this direction includes the gold-nanoparticles that appear to be well absorbed in soft tumour tissues and making the tumour susceptible to radiation (e.g., in the near infrared region) based heat therapy for selective elimination.

Despite the overwhelming understanding of the future prospect of nanomedicine and nano-drug delivery system, its real impact in healthcare system, even in cancer therapy/diagnosis, remains to be very limited. This attributes to the field being a new area of science with only two decades of real research on the subject and many key fundamental attributes still being unknown. The fundamental markers of diseased tissues including key biological markers that allow absolute targeting without altering the normal cellular process is one main future area of research. Ultimately, the application of nanomedicine will advance with our increasing knowledge of diseases at molecular level or that mirrors a nanomaterial-subcellular size comparable marker identification to open up avenues for new diagnosis/therapy. Hence, understanding the molecular signatures of disease in the future will lead to advances in nanomedicine applications. Beyond what we have outlined in this review using the known nanoprobes and nanotheragnostics products, further research would be key for the wider application of nanomedicine.

The concept of controlled release of specific drugs at the beleaguered sites, technology for the assessment of these events, drug’s effect in tissues/cellular level, as well as theoretical mathematical models of predication have not yet been perfected. Numerous studies in nanomedicine areas are centered in biomaterials and formulation studies that appear to be the initial stages of the biomedicine applications. Valuable data in potential application as drug therapeutic and diagnosis studies will come from animal studies and multidisciplinary researches that requires significant amount of time and research resources. With the growing global trend to look for more precise medicines and diagnosis, the future for a more intelligent and multi-centered approach of nanomedicine and nano-drug delivery technology looks bright.

There has been lots of enthusiasm with the simplistic view of development of nanorobots (and nanodevices) that function in tissue diagnosis and repair mechanism with full external control mechanism. This has not yet been a reality and remains a futuristic research that perhaps could be attained by mankind in the very near future. As with their benefits, however, the potential risk of nanomedicines both to humans and the environment at large require long term study too. Hence, proper impact analysis of the possible acute or chronic toxicity effects of new nanomaterials on humans and environment must be analyzed. As nanomedicines gain popularity, their affordability would be another area of research that needs more research input. Finally, the regulation of nanomedicines, as elaborated in the previous section will continue to evolve alongside the advances in nanomedicine applications.

The present review discusses the recent advances in nanomedicines, including technological progresses in the delivery of old and new drugs as well as novel diagnostic methodologies. A range of nano-dimensional materials, including nanorobots and nanosensors that are applicable to diagnose, precisely deliver to targets, sense or activate materials in live system have been outlined. Initially, the use of nanotechnology was largely based on enhancing the solubility, absorption, bioavailability, and controlled-release of drugs. Even though the discovery of nanodrugs deal with high levels of uncertainties, and the discovery of pharmacologically active compounds from natural sources is not a favored option today, as compared to some 50 years ago; hence enhancing the efficacy of known natural bioactive compounds through nanotechnology has become a common feature. Good examples are the therapeutic application of nanotechnology for berberine, curcumin, ellagic acid, resveratrol, curcumin and quercetin. The efficacy of these natural products has greatly improved through the use of nanocarriers formulated with gold, silver, cadmium sulphide, and titanium dioxide polymeric nanoparticles together with solid lipid nanoparticles, crystal nanoparticles, liposomes, micelles, superparamagnetic iron oxide nanoparticles and dendrimers.

There has been a continued demand for novel natural biomaterials for their quality of being biodegradable, biocompatible, readily availability, renewable and low toxicity. Beyond identifying such polysaccharides and proteins natural biopolymers, research on making them more stable under industrial processing environment and biological matrix through techniques such as crosslinking is among the most advanced research area nowadays. Polymeric nanoparticles (nanocapsules and nanospheres) synthesized through solvent evaporation, emulsion polymerization and surfactant-free emulsion polymerization have also been widely introduced. One of the great interest in the development of nanomedicine in recent years relates to the integration of therapy and diagnosis (theranostic) as exemplified by cancer as a disease model. Good examples have been encapsulated such as, oleic acid-coated iron oxide nanoparticles for diagnostic applications through near-infrared; photodynamic detection of colorectal cancer using alginate and folic acid based chitosan nanoparticles; utilization of cathepsin B as metastatic processes fluorogenic peptide probes conjugated to glycol chitosan nanoparticles; iron oxide coated hyaluronic acid as a biopolymeric material in cancer therapy; and dextran among others.

Since the 1990s, the list of FDA-approved nanotechnology-based products and clinical trials has staggeringly increased and include synthetic polymer particles; liposome formulations; micellar nanoparticles; protein nanoparticles; nanocrystals and many others often in combination with drugs or biologics. Even though regulatory mechanisms for nanomedicines along with safety/toxicity assessments will be the subject of further development in the future, nanomedicine has already revolutionized the way we discover and administer drugs in biological systems. Thanks to advances in nanomedicine, our ability to diagnose diseases and even combining diagnosis with therapy has also became a reality.

Abbreviations

Amaranth red

ciliary beat frequency

carbamazepine

colorectal cancer

carboxymethylcellulose

((2-amino-2-carboxyethyl) disulfanyl) nicotinic acid (Cys-MNA)

penetrability and holding

folic acid-conjugated dextran

Food and Drug Administration

ferrous oxide

hyaluronic acid

high density lipoproteins

hydroxypropylmethylcellulose

low density lipoproteins

magnetic resonance

near infrared

nanoparticle

perfluorohexane

repaglidine

antivascular endothelial growth factor

venlafaxine

xanthan gum

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Authors’ contributions

JKP, GD, LFF, EVRC, MDPRT, LSAT, LADT, RG, MKS, SS and SH wrote different sections of the manuscript. JKP, LFF, MDPRT, RG, SS, SH and HSS edited the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Jayanta Kumar Patra and Gitishree Das are grateful to Dongguk University, Republic of Korea for support. Leonardo Fernandes Fraceto and Estefânia V.R. Campos are grateful for the financial support provided by the São Paulo State Research Foundation (FAPESP) and National Council for Scientific and Technological Development (CNPQ). Maria del Pilar Rodriguez-Torres wishes to thank particularly DGAPA UNAM for the postdoctoral scholarship granted. Maria del Pilar Rodriguez-Torres, Laura Susana Acosta-Torres and Luis Armando Diaz-Torres thank Red de Farmoquimicos-CONACYT and DGAPA-UNAM PAPIIT-IN225516 project for support. Renato Grillo would like to thanks the São Paulo State Science Foundation (FAPESP, Grants #2015/26189-8). Han-Seung Shin thank Korea Environmental Industry & Technology Institute (A117-00197-0703-0) and Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through Agricultural-BioTechnology Development Program funded by Ministry of Agriculture, Food and Rural Affairs (MAFRA)(710 003-07-7- SB120, 116075-3) for funding.

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Patra, J.K., Das, G., Fraceto, L.F. et al. Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnol 16 , 71 (2018). https://doi.org/10.1186/s12951-018-0392-8

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Researchers demonstrate metasurfaces that control thermal radiation in unprecedented ways

by CUNY Advanced Science Research Center

Researchers with the Advanced Science Research Center at the CUNY Graduate Center (CUNY ASRC) have experimentally demonstrated that metasurfaces (two-dimensional materials structured at the nanoscale) can precisely control the optical properties of thermal radiation generated within the metasurface itself. This pioneering work, published in Nature Nanotechnology , paves the way for creating custom light sources with unprecedented capabilities, impacting a wide array of scientific and technological applications.

Thermal radiation—a form of electromagnetic waves generated by heat-driven random fluctuations in matter—is inherently broadband in nature, consisting of many colors. A good example is the light emitted by an incandescent bulb. It is also unpolarized, and it spreads out in all directions due to its randomness. These characteristics often limit its utility in applications that require well-defined light properties. In contrast, laser light, known for its defined frequency, polarization, and propagation direction, is well defined, making it invaluable for many key applications of modern society.

Metasurfaces offer a solution for greater utility by controlling electromagnetic waves through meticulously engineered shapes of nanopillars that are arrayed across their surfaces. By varying these structures, researchers can achieve control over light scattering, effectively "shaping" light in customizable ways. So far, however, metasurfaces have only been developed to control laser light sources, and they require bulky, expensive excitation setups.

"Our ultimate aim is enabling metasurface technology that does not require external laser sources, but can provide precise control over the way its own thermal radiation is emitted and propagates," said one of the paper's lead authors, Adam Overvig, formerly a postdoctoral researcher with the CUNY ASRC's Photonics Initiative and currently assistant professor at the Stevens Institute of Technology. "Our work is an important step in this quest, providing the foundation for a new class of metasurfaces that do not require external laser sources, but are fed by internal incoherent oscillations of matter driven by heat."

Unprecedented control over thermal radiation

The research team had previously published theoretical work showing that a properly designed metasurface could shape the thermal radiation it generates, imparting desirable features such as defined frequencies, custom polarization, and even a desired wavefront shape capable of creating a hologram. This study predicted that unlike conventional metasurfaces, a suitably engineered metasurface could both produce and control its own thermal radiation in novel ways.

In the present breakthrough, the team set out to experimentally validate these predictions and build on their new functionalities. The metasurface was achieved by simplifying the previously envisioned device architecture, elegant but challenging to realize, to a single structured layer with a 2D pattern. This streamlined design facilitates easier fabrication and practical implementation.

While conventional thermal radiation is unpolarized, a significant focus of the research was enabling thermal radiation with circularly polarized light, where the electric field oscillates in a rotating manner. Recent works had shown that opposite circular polarizations (rotating respectively with left-handed and right-handed features) could be split into opposite directions, but there seemed to be a fundamental limit to further control the polarization of emitted light.

The team's new design transcends this limitation, allowing for asymmetric emission of circular polarization towards a single direction, demonstrating full control over thermal emission.

"Custom light sources are integral to a number of scientific and technological fields," said Andrea Alù, distinguished professor and Einstein Professor of Physics at The City University of New York Graduate Center and founding director of the CUNY ASRC Photonics Initiative. "The ability to create compact, lightweight sources with desired spectral, polarization, and spatial features is particularly compelling for applications requiring portability, such as space-based technology, field research in geology and biology, and military operations. This work represents a significant step towards realizing these capabilities."

The team noted that the principles applied in their current work can be extended to light-emitting diodes (LEDs), with the potential of enhancing another very common and cheap source of light that is notoriously difficult to control.

Looking ahead, the research team aims to combine these building blocks to achieve more complex thermal emission patterns, such as focusing thermal emission on a specific point above the device or creating a thermal hologram. Such advancements could revolutionize the design and functionality of custom light sources.

Journal information: Nature Nanotechnology

Provided by CUNY Advanced Science Research Center

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• v.8(1); 2018 Jan

Nanotechnology: current uses and future applications in the food industry

Muthu thiruvengadam.

Department of Applied Bioscience, College of Life and Environmental Sciences, Konkuk University, Seoul, 143-701 Republic of Korea

Govindasamy Rajakumar

Ill-min chung.

Recent advances in nanoscience and nanotechnology intend new and innovative applications in the food industry. Nanotechnology exposed to be an efficient method in many fields, particularly the food industry and the area of functional foods. Though as is the circumstance with the growth of any novel food processing technology, food packaging material, or food ingredient, additional studies are needed to demonstrate the potential benefits of nanotechnologies and engineered nanomaterials designed for use in foods without adverse health effects. Nanoemulsions display numerous advantages over conventional emulsions due to the small droplets size they contain: high optical clarity, excellent physical constancy against gravitational partition and droplet accumulation, and improved bioavailability of encapsulated materials, which make them suitable for food applications. Nano-encapsulation is the most significant favorable technologies having the possibility to ensnare bioactive chemicals. This review highlights the applications of current nanotechnology research in food technology and agriculture, including nanoemulsion, nanocomposites, nanosensors, nano-encapsulation, food packaging, and propose future developments in the developing field of agrifood nanotechnology. Also, an overview of nanostructured materials, and their current applications and future perspectives in food science are also presented.

Introduction

Nanoscience and nanotechnology are innovative scientific advancements that have been introduced only in this century. Their utilizations in food and agriculture productions are almost modern compared with that of medicine delivery and pharmaceuticals. Nanotechnology has developed as the scientific advancement to grow and transform the entire agrifood area, with the potential to elevate global food production, furthermore to the nutritional value, quality, and safety of food (Sekhon 2014 ; Chung et al. 2017 ). Nanotechnology uses in food science are going to influence the most important aspects of food manufacturing from food protection to the molecular synthesis of new food products and ingredients (Pathakoti et al. 2017 ). Nanotechnology is expected to facilitate the following development stage of genetically altered crops, input to the production of animal and fisheries, chemical insecticides and precision farming methods. Precision farming is one of the most important techniques utilized for increasing crop productivity by monitoring environmental variables and applying the targeted action (Chen and Yada 2011 ). Food endures a variability of post-harvest- and processing-persuaded changes that affect its biological and biochemical maquillage. Thus, nanotechnology development in the areas of biochemistry and biology could also affect the food manufacturing (Sozer and Kokini 2009 ; Jain et al. 2016 ). There is a need to develop simpler, faster, more sensitive and low-cost approaches for the observation and quantification of impurities in foods. Within the past decade, with remarkable advances in nanoscience, nanotechnology-enabled sensors and systems have been increasingly used to develop rapid and noninvasive methods of detection of food contaminants.

Nanotechnological applications in food industry

Nanotechnology has been reported as the new industrial revolution, both developed, and developing countries are investing in this technology to secure a market share. At present, the USA leads with a 4-year, 3.7-billion USD investment through its National Nanotechnology Initiative (NNI). The USA is followed by Japan and the European Union, which have both committed substantial funds (750 million and 1.2 billion, including individual country contributions, respectively, per year). Others such as India, South Korea, Iran, and Thailand are also catching up with a focus on applications specific to the economic growth and needs of their countries (Kour et al. 2015 ). Food processing approaches that involve nanomaterials include integration of nutraceuticals, gelation and viscosifying agents, nutrient propagation, mineral and vitamin fortification, and nano-encapsulation of flavors (Huang et al. 2010 ). Thus, systems with physical structures in the nanometer distance range could affect features from food safety to molecular synthesis. Nanotechnology may also have the potential to enhance food quality and safety. Many studies are assessing the ability of nanosensors to improve pathogen detection in food systems. Nanofoods are products that were grown processed or packaged with the aid of nanotechnology or materials produced with nanotechnology (Fig.  1 ). In this review, we discuss some current nanotechnology research in food technology and agriculture, including processing, packaging, nano-additives, cleaning, and sensors for the detection of contaminants, and propose future developments in the developing field of agrifood nanotechnology (Fig.  2 ).

Framework for integrating nanoresearch areas and the food supply chain

Different steps of food management that involve several steps (processing, packaging, and preservation) and these aided by nanotechnology with the assistance of several nanomaterials

Nano-delivery of food ingredient

Nanoemulsion.

The emulsion is two or more combination of liquids (oil/water system) that do not simply combine. The diameters of nanoemulsion to discrete droplets measure 500 nm or less. It can contain functional constituents within their droplets, which can ease a decrease in chemical degradation (Ravichandran 2010 ). The promising vicinity of nanotechnology within the food industry is the usage of nanoemulsions as carriers for lipophilic bioactive constituents, flavoring agents, antioxidants, preservatives, and drugs (Silva et al. 2012 ). An interest has been developing in the use of nanoemulsions within the food, beverage, and medicinal industries since they have some potential benefits over conventional emulsions for certain applications (Komaiko and McClements 2016 ). Nanoemulsions are kinetically uniform liquid-in-liquid dispersions with droplet sizes about 100 nm (Komaiko and McClements 2016 ). Nanoemulsion-based delivery system can also improve the bioavailability of the encapsulated components due to the small particle size and high surface-to-volume ratio (Sun et al. 2015 ). As a trendy advice, when used in the food manufacturing nanotechnology needs to be reasonable, easy to utilize, and with willingly perceived benefits in order to be a real another to the normal techniques. There are diverse challenges like limited food-grade stabilizers or other ingredients obtainable. The food industry would like to prepare nanoemulsions from legally acceptable, label-friendly, and economically viable ingredients. The most important is the toxicological concerns because the nanosize of the droplets that could alter the normal function of the gastrointestinal tract (Sugumar and Singh 2016 ). A fascinating food application of essential oils nanoemulsion has been observed in plums. Recently, lemongrass oil nanoemulsion was used to evaluate antimicrobial properties, physical, and chemical changes in plums (Kim et al. 2013 ). The nanoemulsion was able to inhibit E. coli and Salmonella population without altering essence, breakability, and smoothness of the product. It was also able to decrease ethylene production and retard alterations in lightness and concentration of phenolic compounds (Amaral and Bhargava 2015 ).

Nanoemulsions have some potential benefits over traditional emulsions for specific uses within food and beverage products. Nanoemulsions typically have a better consistency about particle accumulation and gravitational separation (Komaiko and McClements 2016 ). Nanoemulsions can be assembled through a variety of approaches, which can be classified as low-energy or high-energy methods depending on the inactive principle (Gupta et al. 2016 ). Various types of nanoemulsions with more complex properties, e.g., nanostructured multilayer emulsions or uncountable emulsions, produce various encapsulating skills from a single delivery system; this can promote the activity of the active components and facilitate their release in response to an activator. For example, Nestle and Unilever have developed a nanoemulsion-based ice cream with less content of fat (Singh 2015 ). Nano-encapsulation of food ingredients and additives had been carried out to provide protecting hurdles, taste and flavor masking, controlled release, and better dispensability for water-insoluble food ingredients and additives. There is a developing public concern regarding the toxicity and adverse effect of nanoparticles on human health and environment (Cushen et al. 2012 ).

Lipid-based nanoemulsions are better for the delivery of constituents within biological systems than traditional nanoemulsions. However, the high lipid content of these nanoemulsions results in adverse effects on the body, such as obesity and cardiovascular diseases (Pradhan et al. 2015 ). Some approaches for forming nanoemulsions using low-energy methods require the presence of cosolvents (e.g., polyols, such as propylene glycol, glycerol, and sorbitol) or cosurfactants (e.g., short and medium-chain alcohols) (McClements and Rao 2011 ). Nanoemulsions present numerous benefits such as cleansing of equipment and high clearness without compromising product presence and flavor (Fig.  3 ). Nano-sized functional molecules that are encapsulated by the self-assembled nanoemulsions are used for targeted delivery of lutein; β-carotene; lycopene; vitamins A, D, and E3; co-enzyme Q10; and omega-3-fatty acids (Choi et al. 2011 ). The use of nanoemulsions to food systems still poses challenges that need to be addressed both concerning the production process, particularly their price and of the characterization of both the resultant nanoemulsions and the food systems to which they will be applied to product safety and acceptance. Nanoemulsions exhibit numerous benefits over traditional emulsions because of their small droplet dimensions: high optical clearness, excellent physical constancy against gravitational partition and droplet accumulation, and improved bioavailability of encapsulated materials, which make them suitable for food applications (Oca-Avalos et al. 2017 ).

Nanofunctional food delivery systems

Nano-encapsulation

Nanotechnology can also facilitate encapsulation of drugs or other components for protection against environmental factors and can be used in the plan of food ingredients, e.g., flavors and antioxidants (Ravichandran 2010 ). Micro-encapsulation is used to increase bioavailability, control release kinetics, minimize drug side effects, and cover the bitter taste of medicinal substances in the pharmaceutical industry. In the food industry, nanoemulsions are used in the organized release of additives and the manufacturing of foods containing functional constituents, such as probiotics and bioactive ingredients (Kuang et al. 2010 ). Currently, numerous techniques of nano-encapsulation are progressively rising with their own merits and demerits. Techniques including emulsification, coacervation, inclusion complexation, nanoprecipitation, solvent evaporation, and supercritical fluid technique are enduring techniques for nano-encapsulation of food substances. Moreover, solvent evaporation and nanoprecipitation remain to be particular techniques for encapsulation of lipophilic bioactive compounds. However, all the encapsulation technologies, in the long run, depend on proper drying strategies to provide nanoencapsulates in powder form. Lee et al. ( 2017 ) conducted a study to improve the water solubility and antimicrobial activity of milk thistle silymarin by nano-encapsulation and to assess the functions of silymarin nanoparticle-containing film as an antimicrobial food-packaging agent. Further, the author stated that the incorporation of silymarin in WCS/-PGA nanoparticles could be an effective approach for improving the solubility and the antimicrobial activity of silymarin. Biodegradable films containing silymarin nanoparticles could efficiently control the growth of food microorganisms. Nano-encapsulation of valuable microorganisms, e.g., probiotics, is advantageous because targeted and site-specific delivery to the desired region of the gastrointestinal tract can be achieved. These nano-encapsulated designer bacterial preparations can be used in vaccine preparation and to enhance the immune response (Vidhyalakshmi et al. 2009 ). Additionally, nanoemulsions have been shown to improve the health benefits of curcumin (Wang et al. 2008 ). Most nanoencapsulates have shown excellent bioavailability, and few encapsulates have reported good inhibitory effect against certain targeted diseases. However, presently, the possible risks of nanomaterials to human fitness are unknown and need to be explored and studied (Ezhilarasi et al. 2013 ). Moreover, the regulatory issues on nanofoods are still being developed, and it is expected that national bodies will increase initiatives to control, administrate, and promote the proper development of nano-sized food-related products.

Packaging of food items

Nanocomposites.

Nanocomposites are mostly exploited in the area of food packaging, as they are eco-friendly and biodegradable. Nanocomposites exhibit extremely multipurpose chemical functionality and are therefore used for the growth of high obstacle properties (Pandey et al. 2013 ). A nanocomposite-based commercialized fertilizer, Guard IN Fresh, helps fruits and vegetables to ripen by scavenging ethylene gas (Gupta and Moulik 2008 ). Nanoclays are made of aluminum silicates, commonly mentioned to as phyllosilicates, and are low-cost, constant, and eco-friendly (Davis et al. 2013 ). The nanocomposite is a multiphase material resulted from the combination of two or more constituents, containing a continuous phase (matrix) and a discontinuous nano-dimensional phase with at least one nano-sized dimension (with less than 100 nm). The development of bio-nanocomposite materials for food packaging is significant not only to reduce the environmental problem, but also to improve the functions of the food packaging materials (Othman 2014 ). Moreover, nanoparticles could impart as their active or intelligent properties to food packaging so that they can preserve the food against external factors and increase the food’s stability through antimicrobial properties and/or responding to environmental changes. In spite of several advantages of nanomaterials, their use in food packaging may cause safety problems to human health since they exhibit different physicochemical properties from their macro-scale chemical counterparts (Hanarvar 2016 ). The usage of nanocomposites for food packaging defends not only food, but also develops the shelf-life of food products and overcomes environmental problems associated with the use of plastics. Most packaging materials are not degradable, and popular biodegradable films have a poor barrier and mechanical properties; therefore, these properties must be significantly improved before these films can replace conventional plastics and help to manage universal waste problems (Sorrentino et al. 2007 ).

Shankar and Rhim ( 2016 ) produced nanocomposite films including PBAT (polybutylene adipate-co-terephthalate) and silver nanoparticles. The maximum plasmonic absorption of silver nanoparticles was detected at 435 nm. Moreover, the dramatic increase in tensile strength and water vapor permeability of the film was attributed to the presence of silver nanoparticles. Altogether, the formulated nanocomposite presented important features to be applied in packaging materials due to their UV-screening and biocidal activities. In addition to the abovementioned benefits, nanomaterials have also been developed continuously to enhance the physical and mechanical properties of packaging in terms of tensile strength, rigidity, gas permeability, water resistance and flame resistance. Aimed at providing those properties above, polymer nanocomposites are the latest materials with an enormous potential for use in the active food packaging industry (Youssef 2013 ). Better use of polymer–nanocomposite in the industry in Europe is going very slowly. The main reasons are the cost price of materials and processing, restrictions due to legislation, acceptance by customers in the market, lack of knowledge about the effectiveness and influence of nanoparticles on the ecological and on human health. The potential risk due to the migration of nanoparticles in food, and balance between the use of biomass for the production of foods (Bratovčić et al. 2015 ). Polymer nanocomposite-based food packaging material with antimicrobial properties is particularly useful due to the high surface-to-volume ratio of nanofillers. In addition, this property increases the surface reactivity of the nano-sized antimicrobial agents compared to the bulk counterpart, making them able to kill microorganisms. The performance properties, for example, mechanical, barrier, thermal, optical, biodegradation, and antimicrobial properties are found in polymer nanocomposites for the packaging applications (Fig.  3 ).

Nanosensors

Nanosensors in conjunction with polymers are used to screen food pathogens and chemicals during storage and transit processes in smart packaging. Additionally, smart packaging confirms the integrity of the food package and authenticity of the food product (Pathakoti et al. 2017 ). Nano-gas sensors, nano-smart dust can be used to detect environmental pollution (Biswal et al. 2012 ). These sensors are composed of compact wireless sensors and transponders. Nanobarcodes are also an efficient mechanism for detection of the quality of agricultural fields (Sonkaria et al. 2012 ). An electrochemical glucose biosensor was nanofabricated by layer-by-layer self-assembly of polyelectrolyte for detection and quantification of glucose (Rivas et al. 2006 ). Nanosensors can detect environmental changes, for example, temperature, humidity, and gas composition, as well as metabolites from microbial growth and byproducts from food degradation (Fig.  4 ). The types of nanosensors used for this purpose include array biosensors, carbon nanotube-based sensors, electronic tongue or nose, microfluidic devices, and nanoelectromechanical systems technology (Sozer and Kokini 2009 ). Polymer nanocomposites from carbon black and polyaniline to detect and identify foodborne pathogens ( Bacillus cereus , Vibrio parahaemolyticus , and Salmonella spp.) based on the specific response patterns for each microorganism, as triggered by different vapors produced during their metabolism (Arshak et al. 2007 ). A liposome-containing nanosensor based on microfluidics showed that the main benefit of microfluidic sensors is their simple arrangement and their capability to identify constituents of interest fast in only microliters (µL) of sample volume (Sozer and Kokini 2009 ). The combination of nanosensors into food packaging has shown in various benefits than traditional sensors for example speed of analysis, enhanced sensitivity, specificity and multiplex systems (sample throughput), reduced cost and assay complexity (Singh et al. 2017 ). The sensors based on nanomaterials (nanosensor), both chemical sensors (chemical nanosensors) and biosensors (nanobiosensors), can be used online and combined into existing industrial process and distribution line or off-line as speedy, simple, and transportable, as well as disposable, sensors for food contaminants (Kuswandi 2017 ).

Different types of nanosensors and examples of their use in the food sector

Nanosensors can also be used to determine the qualities of various foods, including wine, coffee, juice, and milk. The sensors are designed using layer-by-layer macromolecule ultra-thin films that show increases in surface area and 10,000-fold higher sensitivity than the human tongue. Nanosensors can further be fixed to packaging to identify microorganisms contaminating food. The packaged food product does not need to be directed to the laboratory for sampling; instead, the sensors indicate the food quality and can be directly interpreted by consumers based on color changes. Sensors that are typically used sensors in food packaging are gas detectors and time–temperature indicators, including array biosensors, nanoparticles in solution, nanoparticle-based sensors, nano-test strips, electronic noses, and nanocantilevers (Tang et al. 2009 ). The use of nanoparticles to develop nanosensors for detection of food contaminant and pathogens in the food method is another possible use of nanotechnology. Indeed, tailor-made nanosensors for food analysis, flavors or colors, drinking water and clinical diagnostics have been developed (Li and Sheng 2014 ). Nanosensors have also been applied for detection of organophosphates in plants, fruits, and water. Owing to the high water solubility, toxicity, and extensive use of pesticides in agriculture, there is an urgent requirement for highly sensitive and selective analytical systems for residue analysis of these pollutants (Valdés et al. 2009 ). Advances in nanosensor technology were discussed in a recent review highlighting magnetic immune sensors based on biomolecules connected with gold nanoparticles with a broad range of uses in food (Vidotti et al. 2011 ). An SPR-based biosensor was applied for fast identification of Campylobacter jejuni in samples of broiler chickens, and the specificity and sensitivity of distribution antibodies against C. jejuni were tested with Campylobacter and non- Campylobacter bacterial strains. Nanosensors and nano-based smart delivery methods are the uses of nanotechnology that are presently working in the agricultural production to help with fighting viruses and other crop pathogens, as well as to boost the effectiveness of agrochemicals at lower amount proportions (Mousavi and Rezaei 2011 ). Jebel and Almasi ( 2016 ) analyzed the antibacterial effect of ZnO nanoparticles embedded in cellulose films (impacts on E. coli and S. aureus ). They also applied ultrasound treatment to the bacteria and observed remarkable antibacterial performance.

Zhao et al. ( 2011 ) created a rapid, sensitive DNA strip sensor based on gold nanoparticle-labeled oligonucleotide probes to detect Acidovorax avenae subsp. citrulli . Both qualitative and semiquantitative findings of the target DNA were obtained; the qualitative limit of detection of the strip sensor was 4 nM. Oxonica Inc. (USA) developed nanobarcodes for use with dessert items or pellets to be delivered using an altered microscope for anti-counterfeiting determinations. The additional trend in the use of nano-packaging is nano-biodegradable packaging. The usage of nanomaterials to develop bioplastics may allow bioplastics to be used as a replacement for fossil fuel-based plastics for food packaging and carry bags. These devices have been receiving growing attention because the need for detecting and measuring at the molecular, physical and chemical properties of toxins, pollutants, and analytes in general (Table  1 ) (Guo et al. 2015 ; Martínez-Bueno et al. 2017 ). Li and Sheng ( 2014 ) reported the applications of gold nanoparticles and CNTs in food contamination detection. Potential research focus has also been suggested. Nanosensors developed based on the molecularly imprinted polymer technology include those used for the detection of trypsin, glucose, catechol, and ascorbic acid (Pathakoti et al. 2017 ). For human health, nanotechnology has tremendous interest in food detection and will be receiving more and more attention shortly. The food industry is eager to benefit from its revolutionary discovery as much as possible. The purpose of research and development of nanotechnology is to realize the efficient control of the microscopic world. Taking advantage of nanotechnology, researchers are beginning to realize the promising future in the field of biological sensors in food detection.

Table 1

Application of microfluidics lab-on-a-chip devices in the detection of mycotoxins

Food packaging

The biodegradability of a packaging material can be augmented by integrating inorganic elements, for example, mud, into the biopolymeric medium and can be measured with surfactants that are utilized for the alteration of the layered silicate. The use of inorganic elements also makes it possible for food packaging to have multiple functionalities, which could aid in the development of methods to deliver fragile micronutrients within edible capsules (Sorrentino et al. 2007 ). Food packaging is thought to be the main application of nanotechnology in the food industry. The adding of nanoparticles to shaped substances and films has been demonstrated to increase the properties of these materials, mainly durability, temperature resistance, flame resistance, barrier properties, optical properties, and recycling properties. Nano-packaging can also be designed to release enzymes, flavors, antimicrobials, antioxidants, and nutraceuticals to extend shelf-life (Cha and Chinnan 2004 ). Giannakas et al. ( 2016 ) have reported that addition of nanoclays is inducing the antimicrobial properties of PVOH/chitosan films and increases antimicrobial activity up to 44% for NaMMT and up to 53% for OrgMMT. Antimicrobial nanomaterials present an amount of current packaging concept planned to bring the vigorous nanoparticles that can be combined into a food package (Mihindukulasuriya and Lim 2014 ). Nanotechnology uses in the food manufacturing can be exploited to produce stronger tastes and color quality or detect bacteria in packaging, and safety by growing the obstacle properties and holds great potential to offer benefits not just within food products, but also around food products. In fact, nanotechnology introduces new chances for innovation in the food industry fast, but uncertainty and health concerns are also emergent (Sekhon 2014 ).

Benefits of nanomaterials in food packaging uses

Bioactive-packaging materials can aid the oxidation of foodstuffs and avoid the development of off-flavors and unwanted textures. Nonsustainable production, lack of recyclability, and insufficient mechanical and barrier properties are some of the ongoing challenges faced by the food and packaging industries. Although metal and glass are excellent barrier materials that can be used to inhibit undesirable mass transport in food packaging, plastics are still popular due to their lightweight, formability, cost effectiveness, and versatility. Indeed, the packaging industry accounts for more than 40% of all plastic usage, with half of this 40% used for food packaging (Rhim et al. 2013 ). Ravichandran ( 2010 ) revealed that the development of exciting novel nanotechnology products for food packaging, and some antimicrobial films had been introduced to increase the shelf-life of food and dairy products (Fig.  5 ). Moreover, food preservation and food packaging materials have become essential in the food industry. Food spoilage can be detected using nanosensors; thousands of nanoparticles fluoresce in several colors after coming into contact with food pathogens. In our studies of the significance of time in nourishment microbiology, the chief goal of nanosensors was to decrease the time for pathogen detection from days to hours or even minutes (Bhattacharya et al. 2007 ). Packaging prepared with nanosensors can also track either the internal or external circumstances of food products, vessels, and pellets. For example, Opel, which is used to make Opalfilm, containing 50-nm carbon black nanoparticles, was used as a biosensor that could change color in response to food spoilage.

Benefits and risks of nanotechnology applications in food and related products

Bioactive packaging resources necessity to be prepared to maintain bioactive chemicals, for example, probiotics, prebiotics, bioavailable flavonoids, and encapsulated vitamins, under optimal conditions, till they are released in a controlled method into the nourishment product (López-Rubio et al. 2006 ). Carbon nanotubes, which are mostly used as packaging for foods, constantly migrate into foods and can be used to control toxicity on the skin and lungs of human (Mills and Hazafy 2009 ). Lemes et al. ( 2008 ) prepared a nanocomposite with multiwalled carbon nanotubes and the biopolymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate), enhancing its mechanical properties. Several microorganisms produce this polymer as reserve materials, and its use as packaging in food was approved in Europe. Reynolds ( 2007 ) demonstrated that approximately 400–500 nano-packaging products are commercially available, and nanotechnology is expected to be utilized in the manufacturing of 25% of all food packaging within the next generation. An ingestible nano-based track and trace technology was developed by pSiNutria, a division of the nanotechnology company pSivida. Possible pSiNutria products include products to identify pathogens in food for food tracing and preservation and temperature measurements in food storage (Alfadul and Elneshwy 2010 ). The FDA controls nanofoods, and the maximum allowable amounts of nanomaterials in food packaging and organic chemicals are monitored by the Environmental Protection Agency (EPA) in the USA. Though neither the EPA nor the FDA has documented nanomaterials as novel chemicals or have required any new oversight of these materials-based products to engage in early and frequent consultation with the agency (Badgley and Perfecto 2007 ).

Application of nanotechnology in foods and bioactives

Archaeosomes are a type of microbial lipid membrane resistant to oxidation, chemical and enzymatic hydrolysis, low pH, high temperature, and the presence of bile salts due to the hostile living environment of Archaea microbes (Mozafari 2006 ). Canham ( 2007 ) found that the milk protein α-lactalbumin in certain conditions can undergo self-assembly to form tubular nanostructures. Such tubes are thousands of nanometers long, their diameter is 20 nm, and the inner cavity diameter is about 8 nm. These structures are formed in several stages. In the first stage, α-lactalbumin is partially hydrolyzed through the activity of a protease from Bacillus licheniformis . Also, along with other components, several derivatives with molecular masses varying from 10 to 14 kDa are formed. In the presence of calcium ions, this mixture self-assembles into helical tubes. Nanocochleates resulting from soy and calcium have been found to be suitable for the nano-encapsulation of vitamins, omega-3 fatty acids, and lycopene without affecting the organoleptic properties of foods (Joseph and Morrison 2006 ). Dairy products, beverages cereals, and bread are now supplemented with minerals, vitamins, bioactive peptides, probiotics, plant sterols, and antioxidants. Some of these active components are being added to foods as nanoparticles or particles of a few hundred nm in size (Shelke 2008 ). Gupta and Gupta ( 2005 ) demonstrated that nanometer-sized particles could be produced using food-grade biopolymers, e.g., polysaccharides or proteins, by inducing phase separation in mixed biopolymer systems, self-association, or aggregation. Nanoparticles are added to various foods to increase flow properties, color, and stability during processing, or shelf-life. For example, aluminosilicate materials are typically used as anticaking agents in powdered processed foods, whereas anatase titanium dioxide is a normal food whitener and brightener additive employed in sweets, some cheeses, and sauces (Ashwood et al. 2007 ). The applications explored here were particularly chosen because they are the most likely nanofood products to be accepted by consumers in the short term. Thus, food nanotechnology is still young, and the future of this exciting field is still largely uncertain. Regardless of how applications of nanotechnology in the food sector are ultimately marketed, governed, or perceived by the public, it seems clear that the manipulation of matter on the nanoscale will continue to yield exciting and unforeseen products.

Agriculture

Nanotechnology has used for alterations of the genetic structures of crop plants, thereby facilitating their improvement. Nanotechnology may offer in agronomic activities, with particular attention to critical features, challenging matters, and investigation needs for professional risk assessment and management in this developing field (Prasad et al. 2017 ). Nano-fertilizers (nano-coated fertilizers, nano-sized nutrients, or carbon-based nanomaterials or engineered metal-oxide), and nano-pesticides (inorganic nanomaterials or nano-formulations of conventional active ingredients), may provide a targeted/controlled release of agrochemicals, aimed to obtain their fullest biological effectiveness without over-dosage (Iavicoli et al. 2017 ). Smart delivery of foods, a fast specimen of biological and chemical impurity, bioseparation of proteins and nano-encapsulation of nutritional supplements are some of the new areas of nanotechnology for food and agriculture (Sozer and Kokini 2009 ). Reduced biosynthesis of chlorophyll by magnetic nanoparticles of Fe 3 O 4 induced a similar and statistically important decrease of chlorophyll and carotene levels of seedlings in sunflower (Ursache-Oprisan et al. 2011 ). The response of seedlings in Zea mays to the administration of the same range of Fe 3 O 4 NPs concentration caused by the decrease of chlorophyll while the seedlings of Cucurbita pepo showed a minor elevation of chlorophyll contents (Racuciu et al. 2009 ). Thiruvengadam et al. ( 2015 ) reported that silver nanoparticles (AgNPs) could regulate the expression of genes involved in the metabolic pathways of carotenoids, phenolics, and glucosinolate in turnips. However, in addition to plants, nanomaterials can also affect animals, such as Eisenia fetida (earthworms), which evade AgNP-improved soil (Shoults-Wilson et al. 2011 ).

Nano-sized calcium carbonate was prepared by reaction of sodium carbonate and calcium chloride by the reversed-phase microemulsion technique and then loaded with the pesticide validamycin. It exhibited excellent germicidal activity against Rhizoctonia solani than validamycin later 7 days, and the time of the release of validamycin was prolonged to 2 weeks. The loading efficiency, stability, sustained-release performance and excellent ecological compatibility of the substance, the system for its use may be prolonged to another hydrophilic pesticide (Qian et al. 2011 ). Guan and Hubacek ( 2010 ) encapsulated the imidacloprid with a coating of chitosan and sodium alginate via layer-by-layer self-assembly, increasing its growth rate in soil applications. Moreover, as a vehicle for active materials (pesticides, fertilizers, or plant growth regulators), nanoparticles can also be synthesized through catalytic oxidation–reduction. Subsequent use of these materials would decrease the quantity of these active constituents in the environment and reduce the time through which the environment is exposed to the effects of the nanomaterials. Using nanotechnology to create new formulations has revealed significant potential in enlightening the efficiency and security of pesticides. The improvement of nano-based pesticide formulation aims at the complete release of necessary and adequate amounts of their active constituents in responding to environmental triggers and biological demands through controlled release mechanisms (Zhao et al. 2017 ). The nanoparticle-mediated transformation has the potential for genetic changes of plants for further development. The use of nanotechnology in plant pathology goals exact agricultural difficulties in plant–pathogen interactions and bring new ways for crop protection. Nair et al. ( 2010 ) studied the delivery of nanoparticulate materials to plants and their eventual effects, which could deliver some perceptions for the safe use of this novel technology for the improvement of crops. Some potential applications of nanoscale science, engineering, and nanotechnology for agriculture, expressly designed to improve and to protect agronomic yields and crop production as well as to detect and remediate environmental pollutants, have been addressed with attention focused on emerging occupational risks in this field (Iavicoli et al. 2017 ).

Conclusions

In conclusion, nanotechnology has become progressively important in the food industry. Food innovation is observed as one of the sector areas in which nanotechnology will play a major part in the forthcoming. New and future innovation is nanotechnology that has exceptionally extraordinary property in food source chain (precision farming techniques, smart feed, enhancement of food texture and quality, bioavailability/nutrient values, packaging, labeling, crop production and use of agrochemicals such as nano-pesticides, nano-fertilizers, and nano-herbicides) round the world agricultural sector. Nanofood packaging resources may widen nourishment life, upgrade food safety, prepared customers that food is sullied or destroyed, repair tears in packaging, and uniform release added substances to grow the life of the food in the package. To maintain leadership in food and food-processing industry, one must work with nanotechnology and nanobio-info in the future. The future belongs to new products and new processes with the goal to customize and personalize the products. Improving the safety and quality of food will be the first step. Finally, nanotechnology enables to change the existing food systems and processing to ensure products safety, creating a healthy food culture, and enhancing the nutritional quality of food.

Acknowledgements

This paper was supported by the KU Research Professor Program of Konkuk University, Seoul, South Korea.

Compliance with ethical standards

Conflict of interest.

The authors have declared that there is no conflict of interest.

Contributor Information

Govindasamy Rajakumar, Email: rk.ca.kuknok@rdnivog .

Ill-Min Chung, Email: rk.ca.kuknok@micmi .

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