journal of nanoparticle research

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Journal of nanoparticle research.

An Interdisciplinary Forum for Nanoscale Science and Technology

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About this journal

The Journal of Nanoparticle Research is a monthly peer-reviewed journal that explores the specific concepts, properties, phenomena and processes of structures at the nanoscale.

Coverage includes synthesis, assembly, transport, reactivity, and stability, and emphasizes realization and application of systems, structures and devices with novel functions obtained via precursor nanoparticles. The Journal fosters the interdisciplinary dissemination of knowledge by encouraging synergetic approaches originating from a wide range of disciplines, such as Physics, Chemistry, Biology and Health Care.

Perspectives now available for free online Perspective articles have a wide breadth of appeal because they evaluate research, industrial and societal trends centered around nanotechnology. See the bigger picture!

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Polymeric nanoparticles as therapeutic agents against coronavirus disease

The technology for improving stability of nanosuspensions in drug delivery, bioactive nano-selenium antagonizes cobalt nanoparticle-mediated oxidative stress via the keap1-nrf2-are signaling pathway.

AbstractAt present, no effective treatment exists for the clinical toxicity of cobalt nanoparticles (CoNPs, 30 nm) after metal-on-metal (MOM) artificial joint replacement. As such, a better understanding of the CoNPs-toxicity mechanism is necessary and urgent for the development of effective and safe detoxification drugs. Our purpose was to explore the role of bioactive nano-selenium (BNS, > 97%) in antagonizing the toxicity of CoNPs and its mechanism through the Keap1-Nrf2-ARE signaling pathway. To examine BNS detoxification, we exposed HUVEC cells to CoNPs and BNS for 24 h, before measuring cell activity, reactive oxygen species (ROS), the GSH level, inflammatory factors, and KNA signaling pathway-related transcript and protein expression. CoNPs stimulate intracellular inflammation and ROS production to bring about significant downregulation of cellular activity and the GSH level. Conversely, BNS reduces ROS generation and suppresses inflammatory factors within cells to reduce CoNPs-mediated cytotoxicity, possibly via the KNA signaling pathway. Based on our results, BNS antagonizes CoNPs toxic effects by suppressing ROS production through the KNA pathway. Our research provides new insight into the clinical treatment of CoNPs toxicity and explores the potential of BNS in detoxification therapy. Trial registration: no human participant.

Hydrated zirconia nanoparticles as media for electrical charge accumulation

A mn-doped calcium phosphate nanoparticle-based multifunctional nanocarrier for targeted drug delivery and cellular mr imaging, palladium nanoparticles supported on aluminum oxide (al2o3) for the catalytic hexavalent chromium reduction, a novel ag nanoparticles purification method and the conductive ink based on the purified ag nanoparticles for printed electronics, use of magnesium nanomaterials in plants and crop pathogens, cu2o/cuo heterojunction formed by thermal oxidation and decorated with pt co-catalyst as an efficient photocathode for photoelectrochemical water splitting, vapor–liquid-solid silicon wires’ synthesis catalyzed by a low-surface tension post-transition metal: effect of process parameters, export citation format, share document.

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Journal of Nanoparticle Research

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The objective of the Journal of Nanoparticle Research is to disseminate knowledge of the physical, chemical and biological phenomena and processes in structures that have at least one lengthscale ranging from molecular to approximately 100 nm (or submicron in some situations), and exhibit improved and novel properties that are a direct result of their small size. Nanoparticle research is a key component of nanoscience, nanoengineering and nanotechnology. For the full aims and scope, please visit the journal website.

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A review on nanoparticles: characteristics, synthesis, applications, and challenges

The significance of nanoparticles (NPs) in technological advancements is due to their adaptable characteristics and enhanced performance over their parent material. They are frequently synthesized by reducing metal ions into uncharged nanoparticles using hazardous reducing agents. However, there have been several initiatives in recent years to create green technology that uses natural resources instead of dangerous chemicals to produce nanoparticles. In green synthesis, biological methods are used for the synthesis of NPs because biological methods are eco-friendly, clean, safe, cost-effective, uncomplicated, and highly productive. Numerous biological organisms, such as bacteria, actinomycetes, fungi, algae, yeast, and plants, are used for the green synthesis of NPs. Additionally, this paper will discuss nanoparticles, including their types, traits, synthesis methods, applications, and prospects.

1. Introduction

Nanotechnology evolved as the achievement of science in the 21st century. The synthesis, management, and application of those materials with a size smaller than 100 nm fall under the interdisciplinary umbrella of this field. Nanoparticles have significant applications in different sectors such as the environment, agriculture, food, biotechnology, biomedical, medicines, etc. like; for treatment of waste water ( Zahra et al., 2020 ), environment monitoring ( Rassaei et al., 2011 ), as a functional food additives ( Chen et al., 2023 ), and as a antimicrobial agents ( Islam et al., 2022 ). Cutting-edge properties of NPs such as; nature, biocompatibility, anti-inflammatory and antibacterial activity, effective drug delivery, bioactivity, bioavailability, tumor targeting, and bio-absorption have led to a growth in the biotechnological, and applied microbiological applications of NPs.

A particle of matter with a diameter of one to one hundred nanometers (nm) is commonly referred to as a nanoparticle or ultrafine particle. Nanoparticles frequently exhibit distinctive size-dependent features, mostly due to their tiny size and colossal surface area. The periodic boundary conditions of the crystalline particle are destroyed when the size of a particle approaches the nano-scale with the characteristic length scale close to or smaller than the de Broglie wavelength or the wavelength of light ( Guo et al., 2013 ). Because of this, many of the physical characteristics of nanoparticles differ significantly from those of bulk materials, leading to a wide range of their novel uses ( Hasan, 2015 ).

2. Emergence of nanotechnology

Nanotechnology emerged in the 1980s due to the convergence of experimental advances such as the invention of the scanning tunneling microscope in 1981 and the discovery of fullerenes in 1985 ( Bayda et al., 2019 ), with the elucidation. The popularization of a conceptual framework for nanotechnology goals began with the publication of the book Engines of Creation in 1986 ( Bayda et al., 2019 ).

2.1. Early stage of NPs

Carbon nanotubes have been discovered in pottery from Keeladi, India, dating from around 600–300 BC ( Bayda et al., 2019 ; Kokarneswaran et al., 2020 ). Cementite nanowires have been discovered in Damascus steel, a material that dates back to around 900 AD; nevertheless, its origin and creation method are unclear ( Kokarneswaran et al., 2020 ). However, it is unknown how they developed or whether the material containing them was used on purpose.

2.2. Discovery of C, Ag, Zn, Cu, and Au nanoparticles

Carbon NPs were found in 1991, and Iijima and Ichihashi announced the single-wall carbon nanotube synthesis with a diameter of 1 nanometer in 1993 ( Chen et al., 2021 ). Carbon nanotubes (CNTs), also known as Bucky tubes, are a kind of nanomaterial made up of a two-dimensional hexagonal lattice of carbon atoms. They are bent one way and joined to produce a hollow cylindrical cylinder. Carbon nanotubes are carbon allotropes that fall between Fullerene (0 dimensional) and Grapheme (2 dimensional) ( Chen et al., 2021 ).

In addition, M. C. Lea reported that the synthesis of citrate-stabilized silver colloid almost 120 years ago ( Nowack et al., 2011 ). This process produces particles with an average diameter of 7 to 9 nm. Nanoscale size and citrate stabilization are analogous to recent findings on nanosilver production employing silver nitrate and citrate ( Majeed Khan et al., 2011 ). The use of proteins to stabilize nanosilver has also been documented as early as 1902 ( Nowack et al., 2011 ; Beyene et al., 2017 ). Since 1897, a nanosilver known as “Collargol” has been made commercially and used for medicinal purposes ( Nowack et al., 2011 ). Collargol, a type of silver nanoparticle, has a particle size of about 10 nanometers (nm). This was determined as early as 1907, and it was found that the diameter of Collargol falls within the nanoscale range. In 1953, Moudry developed a different type of silver nanoparticle called gelatin-stabilized silver nanoparticles, with a diameter ranging from 2–20 nm. These nanoparticles were produced using another method than Collargol. The necessity of nanoscale silver was recognized by the creators of nanosilver formulations decades ago, as seen by the following remark from a patent: “for optimal efficiency, the silver must be disseminated as particles of colloidal size less than 25 nm in crystallite size”( Nowack et al., 2011 ).

Gold NPs (AuNPs) have a long history in chemistry, going back to the Roman era when they were used to decorate glassware by staining them. With the work of Michael Faraday, who may have been the first to notice that colloidal gold solutions have characteristics different from bulk gold, the contemporary age of AuNP synthesis began more than 170 years ago. Michael Faraday investigated the making and factors of colloidal suspensions of “Ruby” gold in 1857. They are among the magnetic nanoparticles due to their distinctive optical and electrical characteristics. Under specific illumination circumstances, Faraday showed how gold nanoparticles might create solutions of various colors ( Bayda et al., 2019 ; Giljohann et al., 2020 ).

3. Classification of NPs

Nanoparticles (NPs) are categorized into the following classes based on their shape, size, and chemical characteristics;

3.1. Carbon-based NPs

Fullerenes and carbon nanotubes (CNTs) are the two essential sub-categories of carbon-based NPs. NPs of globular hollow cages, like allotropic forms of carbon, are found in fullerenes. Due to their electrical conductivity, high strength, structure, electron affinity, and adaptability, they have sparked significant economic interest. These materials have organized pentagonal and hexagonal carbon units, each of which is sp2 hybridized. While CNTs are elongated and form 1–2 nm diameter tubular structures. These fundamentally resemble graphite sheets rolling on top of one another. Accordingly, they are referred to as single-walled (SWNTs), double-walled (DWNTs), or multi-walled carbon nanotubes (MWNTs) depending on how many walls are present in the rolled sheets ( Elliott et al., 2013 ; Astefanei et al., 2015 ).

3.2. Metal NPs

Metal NPs are purely made of metals. These NPs have distinctive electrical properties due to well-known localized surface Plasmon resonance (LSPR) features. Cu, Ag, and Au nanoparticles exhibit a broad absorption band in the visible region of the solar electromagnetic spectrum. Metal NPs are used in several scientific fields because of their enhanced features like facet, size, and shape-controlled synthesis of metal NPs ( Khan et al., 2019 ).

3.3. Ceramics NPs

Ceramic NPs are tiny particles made up of inorganic, non-metallic materials that are heat-treated and cooled in a specific way to give particular properties. They can come in various shapes, including amorphous, polycrystalline, dense, porous, and hollow, and they are known for heat resistance and durable properties. Ceramic NPs are used in various applications, including coating, catalysts, and batteries ( Sigmund et al., 2006 ).

3.4. Lipid-based NPs

These NPs are helpful in several biological applications because they include lipid moieties. Lipid NPs typically have a diameter of 10–1,000 nm and are spherical. Lipid NPs, i.e., polymeric NPs, have a solid lipid core and a matrix consisting of soluble lipophilic molecules ( Khan et al., 2019 ).

3.5. Semiconductor NPs

Semiconductor NPs have qualities similar to metals and non-metals. That is why Semiconductor NPs have unique physical and chemical properties that make them useful for various applications. For example, semiconductor NPs can absorb and emit light and can be used to make more efficient solar cells or brighter light-emitting diodes (LEDs). They can make smaller and faster electronic devices, such as transistors, and can be used in bio imaging and cancer therapy ( Biju et al., 2008 ).

3.6. Polymeric NPs

Polymeric NPs with a size between 1 and 1,000 nm can have active substances surface-adsorbed onto the polymeric core or entrapped inside the polymeric body. These NPs are often organic, and the term polymer nanoparticle (PNP) is commonly used in the literature to refer to them. They resemble Nano spheres or Nano capsules for the most part ( Khan et al., 2019 ; Zielińska et al., 2020 ).

4. Types of different metal-based NPs

Metal NPs are purely made of metal precursors. Due to well-known localized surface plasmon resonance (LSPR) characteristics, these NPs possess unique optoelectrical properties. NPs of the alkali and noble metals, i.e., Cu, Ag, and Au, have a broad absorption band in the visible zone of the solar electromagnetic spectrum. The facet, size, and shape-controlled synthesis of metal NPs are essential in present-day cutting-edge materials ( Dreaden et al., 2012 ; Khan et al., 2019 ).

4.1. Silver nanoparticles (AgNPs)

AgNPs are particles with a size range of 1–100 nanometers made of silver. They have unique physical and chemical properties due to their small size, high surface area-to-volume ratio, and ability to absorb and scatter light in the visible and near-infrared range. Because of their relatively small size and high surface-to-volume ratios, which cause chemical and physical differences in their properties compared to their bulk counterparts, silver nanoparticles may exhibit additional antimicrobial capabilities not exerted by ionic silver ( Shenashen et al., 2014 ).

Besides, AgNPs can be created in various sizes and forms depending on the manufacturing process, the most common of which is chemical reduction. The AgNPs were created by chemically reducing a 12 mM AgNO3 aqueous solution. The reaction was carried out in an argon environment using 70 mL of this solution containing PVP (keeping the molar ratio of the repeating unit of PVP and Ag equal to 34) and 21 mL of Aloe Vera. The mixture was agitated in ultrasonic for 45 min at ambient temperature, then heated 2°C/min to 80°C and left for 2 h to generate a transparent solution with tiny suspended particles that must be removed by simple filtering ( Shenashen et al., 2014 ; Gloria et al., 2017 ).

4.2. Zinc nanoparticles (ZnONPs)

Zinc nanoparticles (ZnONPs) are particles with a size range of 1–100 nm made of zinc. Zinc oxide (ZnO) NPs are a wide band gap semiconductor with a room temperature energy gap of 3.37 eV. Its catalytic, electrical, optoelectronic, and photochemical capabilities have made it widely worthwhile ( Kumar S.S. et al., 2013 ). ZnO nanostructures are ideal for catalytic reaction processes ( Chen and Tang, 2007 ). Laser ablation, hydrothermal methods, electrochemical depositions, sol-gel method, chemical vapor deposition, thermal decomposition, combustion methods, ultrasound, microwave-assisted combustion method, two-step mechanochemical-thermal synthesis, anodization, co-precipitation, electrophoretic deposition, and precipitation processes are some methods for producing ZnO nanoparticles ( Madathil et al., 2007 ; Moghaddam et al., 2009 ; Ghorbani et al., 2015 ).

4.3. Copper nanoparticles (CuNPs)

Copper nanoparticles (CuNPs) comprise a size range of 1–100 nm of copper-based particles ( Khan et al., 2019 ). Cu and Au metal fluorescence have long been known to exist. For excitation at 488 nm, a fluorescence peak centering on the metals’ interband absorption edge has been noted. Additionally, it was noted that the fluorescence peaked at the same energy at two distinct excitation wavelengths (457.9–514.5 and 300–400 nm), and the high-energy tail somewhat grows with increased photon energy pumping. A unique, physical, top-down EEW approach has been used to create Cu nanoparticles. The EEW method involves sending a current of *1,010 A/m2 (1,010 A/m2) across a thin Cu wire, which explodes on a Cu plate for a duration of 10–6 s ( Siwach and Sen, 2008 ).

4.4. Gold nanoparticles (AuNPs)

Gold nanoparticles(AuNPs) are nanometers made of gold. They have unique physical and chemical properties and can absorb and scatter light in the visible and near-infrared range ( Rad et al., 2011 ; Compostella et al., 2017 ).

Scientists around the turn of the 20th century discovered anisotropic AuNPs. Zsigmond ( Li et al., 2014 ) said that gold particles “are not always spherical when their size is 40 nm or lower” in his book, released in 1909. Additionally, he found anisotropic gold particles of various colors. Zsigmondy won the Nobel Prize in 1925 for “his demonstration of the heterogeneous character of colloidal solutions and the methods he utilized” and for developing the ultramicroscope, which allowed him to see the forms of Au particles. He noticed that gold frequently crystallized into a six-sided leaf shape ( Li et al., 2014 ).

AuNPs are the topic of extensive investigation due to their optical, electrical, and molecular-recognition capabilities, with numerous prospective or promised uses in a wide range of fields, including electron microscopy, electronics, nanotechnology, materials science, and biomedicine ( Rad et al., 2011 ).

4.5. Aluminum nanoparticles (AlNPs)

Aluminum nanoparticles (AlNPs) are nanoparticles made of aluminum. Aluminum nanoparticles’ strong reactivity makes them promising for application in high-energy compositions, hydrogen generation in water processes, and the synthesis of alumina 2D and 3D structures ( Lerner et al., 2016 ).

4.6. Iron nanoparticles (FeNPs)

Iron nanoparticles(FeNPs) are particles with a size range of 1−100 nanometers ( Khan et al., 2019 ) made of iron. FeNPs have several potential applications, including their use as catalysts, drug delivery systems, sensors, and energy storage and conversion. They have also been investigated for use in photovoltaic and solar cells and water purification and environmental remediation. FeNPs can also be used in magnetic resonance imaging (MRI) as contrast agents to improve the visibility of tissues and organs. They can also be used in magnetic recording media, such as hard disk drives ( Zhuang and Gentry, 2011 ; Jamkhande et al., 2019 ).

As with any NPs, there are potential health and safety concerns associated with using FeNPs, e.g., FeNPs are used to deliver drugs to specific locations within the body, such as cancer cells and used in MRI, and used to remove contaminants from water ( Farrell et al., 2003 ; Zhuang and Gentry, 2011 ). Tables 1 , ​ ,2 2 show the characteristics of metal-based nanoparticles and the techniques to study their characteristics, respectively.

Characteristics of metal based nanoparticles.

Different analytical techniques and their purposes in studying nanoparticles.

5. Approaches for the synthesis of metal NPs

There are mainly three types of approaches for the synthesis of NPs: the physical, chemical, and biological approaches. The physical approach is also called the top-down approach, while chemical and biological approaches are collectively called the bottom-up approach. The biological approach is also named green systems of NPs. All these approaches are further sub-categorized into various types based upon their method adopted. Figure 1 illustrates each approach’s reported methods for synthesizing NPs.

Approaches of NPs synthesis.

5.1. Top down/physical approach

Bulk materials are fragmented in top-down methods to create nano-structured materials ( Figure 2 ). They are additionally known as physical approaches ( Baig et al., 2021 ). The following techniques can achieve a top-down approach;

Difference between top-down and bottom-up approaches.

5.1.1. Mechanical milling

The mechanical milling process uses balls inside containers and may be carried out in various mills, typically planetary and shaker mills, which is an impact process with high energy ( Gorrasi and Sorrentino, 2015 ). Mechanical milling is a practical approach for creating materials at the nanoscale from bulk materials. Aluminum alloys that have been strengthened by oxide and carbide, spray coatings that are resistant to wear, nanoalloys based on aluminum, nickel, magnesium, and copper, and a variety of other nanocomposite materials may all be created mechanically. A unique class of nanoparticles known as ball-milled carbon nanomaterials has the potential to meet the needs for energy storage, energy conversion, and environmental remediation ( Yadav et al., 2012 ; Lyu et al., 2017 ).

5.1.2. Electrospinning

Typically, it is used to create nanofibers from various materials, most often polymers ( Ostermann et al., 2011 ). A technique for creating fibers called electrospinning draws charged threads from polymer melts or solutions up to fiber sizes of a few hundred nanometers ( Chronakis, 2010 ). Coaxial electrospinning was a significant advancement in the field of electrospinning. The spinneret in coaxial electrospinning is made up of two coaxial capillaries. Core-shell nanoarchitectures may be created in these capillaries using two viscous liquids, a viscous liquid as the shell and a non-viscous liquid as the core ( Du et al., 2012 ). Core-shell and hollow polymer, inorganic, organic, and hybrid materials have all been developed using this technique ( Kumar R. et al., 2013 ).

5.1.3. Laser ablation

A microfeature can be made by employing a laser beam to vaporize a single material ( Tran and Wen, 2014 ). Laser ablation synthesis produces nanoparticles by striking the target material with an intense laser beam. Due to the high intensity of the laser irradiation used in the laser ablation process, the source material or precursor vaporizes, causing the production of nanoparticles ( Amendola and Meneghetti, 2009 ). Laser ablation is an environmentally friendly for producing noble metal nanoparticles ( Baig et al., 2021 ). This method may be used to create a wide variety of nanomaterials, including metal nanoparticles, carbon nanomaterials, oxide composites, and ceramics ( Su and Chang, 2018 ; Baig et al., 2021 ).

5.1.4. Sputtering

Microparticles of a solid material are expelled off its surface during the phenomenon known as sputtering, which occurs when the solid substance is assaulted by intense plasma or gas particles ( Behrisch, 1981 ). According to the incident gaseous ion energy, energetic gaseous ions used in the sputtering deposition process physically expel tiny atom clusters off the target surface ( Muñoz-García et al., 2009 ). The sputtering method is intriguing because it is more affordable than electron-beam lithography, and the composition of the sputtered nanomaterials is similar to the target material with fewer contaminants ( Baig et al., 2021 ).

5.1.5. Electron explosion

In this technique, a thin metal wire is subjected to a high current pulse that causes an explosion, evaporation, and ionization. The metal becomes vaporized and ionized, expands, and cools by reacting with the nearby gas or liquid medium. The condensed vapor finally forms the nanoparticles ( Joh et al., 2013 ). Electron explosion method because it produces plasma from the electrical explosion of a metallic wire, which may produce nanoparticles from a Pt solution without using a reducing agent ( Joh et al., 2013 ).

5.1.6. Sonication

The most crucial step in the creation of nanofluids is sonication. After the mixture has been magnetically stirred in a magnetic stirrer, sonication is performed in an ultrasonication path, ultrasonic vibrator, and mechanical homogenizer. Sonicators have become the industry standard for Probe sonication and are noticeably more powerful and effective when compared to ultrasonic cleaner baths for nanoparticle applications. Probe sonication is highly effective for processing nanomaterials (carbon nanotubes, graphene, inks, metal oxides, etc.) ( Zheng et al., 2010 ).

5.1.7. Pulsed wire discharge method

This is the most used method for creating metal nanoparticles. A pulsating current causes a metal wire to evaporate, producing a vapor that is subsequently cooled by an ambient gas to form nanoparticles. This plan may quickly produce large amounts of energy ( Patil et al., 2021 ).

5.1.8. Arc discharge method

Two graphite rods are adjusted in a chamber with a constant helium pressure during the Arc Discharge procedure. It is crucial to fill the chamber with helium because oxygen or moisture prevents the synthesis of fullerenes. Arc discharge between the ends of the graphite rods drives the vaporization of carbon rods. Achieving new types of nanoparticles depends significantly on the circumstances in which arc discharge occurs. The creation of several nanostructured materials may be accomplished with this technique ( Berkmans et al., 2014 ). It is well-recognized for creating carbon-based materials such as fullerenes, carbon nanohorns (CNHs), carbon nanotubes ( Shi et al., 2000 ), few-layer graphene, and amorphous spherical carbon nanoparticles ( Kumar R. et al., 2013 ).

5.1.9. Lithography

Lithography typically uses a concentrated beam of light or electrons to create nanoparticles, a helpful technique ( Pimpin and Srituravanich, 2012 ). Masked and maskless lithography are the two primary categories of lithography. Without a mask, arbitrary nano-pattern printing is accomplished in maskless lithography. Additionally, it is affordable and easy to apply ( Brady et al., 2019 ).

5.2. Bottom-up approach

Tiny atoms and molecules are combined in bottom-up methods to create nano-structured particles ( Figure 2 ; Baig et al., 2021 ). These include chemical and biological approaches:

5.2.1. Chemical vapor deposition (CVD)

Through a chemical process involving vapor-phase precursors, a thin coating is created on the substrate surface during CVD ( Dikusar et al., 2009 ). Precursors are deemed appropriate for CVD if they exhibit sufficient volatility, high chemical purity, strong evaporation stability, cheap cost, a non-hazardous nature, and long shelf life. Additionally, its breakdown should not leave behind any contaminants. Vapor phase epitaxy, metal-organic CVD, atomic layer epitaxy, and plasma-enhanced CVD are only a few CVD variations. This method’s benefits include producing very pure nanoparticles that are stiff, homogeneous, and strong ( Ago, 2015 ). CVD is an excellent approach to creating high-quality nanomaterials ( Machac et al., 2020 ). It is also well-known for creating two-dimensional nanoparticles ( Baig et al., 2021 ).

5.2.2. Sol-gel process

A wet-chemical approach, called the sol-gel method, is widely utilized to create nanomaterials ( Das and Srivasatava, 2016 ; Baig et al., 2021 ). Metal alkoxides or metal precursors in solution are condensed, hydrolyzed, and thermally decomposed. The result is a stable solution or sol. The gel gains greater viscosity as a result of hydrolysis or condensation. The particle size may be seen by adjusting the precursor concentration, temperature, and pH levels. It may take a few days for the solvent to be removed, for Ostwald ripening to occur, and for the phase to change during the mature stage, which is necessary to enable the growth of solid mass. To create nanoparticles, the unstable chemical ingredients are separated. The generated material is environmentally friendly and has many additional benefits thanks to the sol-gel technique ( Patil et al., 2021 ). The uniform quality of the material generated, the low processing temperature, and the method’s ease in producing composites and complicated nanostructures are just a few of the sol-gel technique’s many advantages ( Parashar et al., 2020 ).

5.2.3. Co-precipitation

It is a solvent displacement technique and is a wet chemical procedure. Ethanol, acetone, hexane, and non-solvent polymers are examples of solvents. Polymer phases can be either synthetic or natural. By mixing the polymer solution, fast diffusion of the polymer-solvent into the non-solvent phase of the polymer results. Interfacial stress at two phases results in the formation of nanoparticles ( Das and Srivasatava, 2016 ). This method’s natural ability to produce high quantities of water-soluble nanoparticles through a straightforward process is one of its key benefits. This process is used to create many commercial iron oxide NP-based MRI contrast agents, including Feridex, Reservist, and Combidex ( Baig et al., 2021 ; Patil et al., 2021 ).

5.2.4. Inert gas condensation/molecular condensation

Metal NPs are produced using this method in large quantities. Making fine NPs using the inactive gas compression approach has been widespread, which creates NPs by causing a metallic source to disappear in an inert gas. At an attainable temperature, metals evaporate at a tolerable pace. Copper metal nanoparticles are created by vaporizing copper metal inside a container containing argon, helium, or neon. The atom quickly loses its energy by cooling the vaporized atom with an inert gas after it boils out. Liquid nitrogen is used to cool the gases, forming nanoparticles in the range of 2–100 nm ( Pérez-Tijerina et al., 2008 ; Patil et al., 2021 ).

5.2.5. Hydrothermal

In this method, for the production of nanoparticles, hydrothermal synthesis uses a wide temperature range from ambient temperature to extremely high temperatures. Comparing this strategy to physical and biological ones offers several benefits. At higher temperature ranges, the nanomaterials produced by hydrothermal synthesis could become unstable ( Banerjee et al., 2008 ; Patil et al., 2021 ).

5.2.6. Green/biological synthesis

The synthesis of diverse metal nanoparticles utilizing bioactive agents, including plant materials, microbes, and various biowastes like vegetable waste, fruit peel waste, eggshell, agricultural waste, algae, and so on, is known as “green” or “biological” nanoparticle synthesis ( Kumari et al., 2021 ). Developing dependable, sustainable green synthesis technologies is necessary to prevent the formation of undesirable or dangerous byproducts ( Figure 3 ). The green synthesis of nanoparticles also has several advantages, including being straightforward, affordable, producing NPs with high stability, requiring little time, producing non-toxic byproducts, and being readily scaled up for large-scale synthesis ( Malhotra and Alghuthaymi, 2022 ).

Schematic diagram for biosynthesis of NPs.

5.2.6.1. Biological synthesis using microorganisms

Microbes use metal capture, enzymatic reduction, and capping to create nanoparticles. Before being converted to nanoparticles by enzymes, metal ions are initially trapped on the surface or interior of microbial cells ( Ghosh et al., 2021 ). Use of microorganisms (especially marine microbes) for synthesis of metalic NPs is environmental friendly, fast and economical ( Patil and Kim, 2018 ). Several microorganisms are used in the synthesis of metal NPs, including:

Biosynthesis of NPs by bacteria: A possible biofactory for producing gold, silver, and cadmium sulfide nanoparticles is thought to be bacterial cells. It is known that bacteria may produce inorganic compounds either inside or outside of their cells ( Hulkoti and Taranath, 2014 ). Desulforibrio caledoiensis ( Qi et al., 2013 ), Enterococcu s sp. ( Rajeshkumar et al., 2014 ), Escherichia coli VM1 ( Maharani et al., 2016 ), and Ochrobactrum anhtropi ( Thomas et al., 2014 ) based metal NPs are reported previously for their potential photocatalytic properties ( Qi et al., 2013 ), antimicrobial activity ( Rajeshkumar et al., 2014 ), and anticancer activity ( Maharani et al., 2016 ).

Extracellular synthesis of NPs by bacteria: The microorganisms’ extracellular reductase enzymes shrink the silver ions to the nanoscale range. According to protein analysis of microorganisms, the NADH-dependent reductase enzyme carries out the bio-reduction of silver ions to AgNPs. The electrons for the reductase enzyme come from NADH, which is subsequently converted to NAD+. The enzyme is also oxidized simultaneously when silver ions are reduced to nanosilver. It has been noted that bio-reduction can occasionally be caused by nitrate-dependent reductase. The decline occurs within a few minutes in the quick extracellular creation of nanoparticles ( Mathew et al., 2010 ). At pH 7, the bacterium R. capsulata produced gold nanoparticles with sizes ranging from 10−20 nm. Numerous nanoplates and spherical gold nanoparticles were produced when the pH was changed to four ( Sriram et al., 2012 ). By adjusting the pH, the gold nanoparticles’ form may be changed. Gold nanoparticle shape was controlled by regulating the proton content at various pH levels. The bacteria R. capsulata ’s release cofactor NADH and NADH-dependent enzymes may cause the bioreduction of Au (3+) to Au (0) and the generation of gold nanoparticles. By using NADH-dependent reductase as an electron carrier, it is possible to start the reduction of gold ions ( Sriram et al., 2012 ).

Intracellular synthesis of NPs by bacteria: Three processes are involved in the intracellular creation of NPs: trapping, bioreduction, and capping. The cell walls of microorganisms and ions charge contribute significantly to creating NPs in the intracellular route. This entails specific ion transit in the presence of enzymes, coenzymes, and other molecules in the microbial cell. Microbes have a range of polysaccharides and proteins in their cell walls, which function as active sites for the binding of metal ions ( Slavin et al., 2017 ). Not all bacteria can produce metal and metal oxide nanoparticles. The only ions that pose a significant hazard to microorganisms are heavy metal ions, which, in response to a threat, cause the germs to react by grabbing or trapping the ions on the cell wall via electrostatic interactions. This occurs because a metal ion is drawn to the cell wall’s carboxylate groups, including cysteine and polypeptides, and certain enzymes with a negative charge ( Zhang et al., 2011 ).

Additionally, the electron transfers from NADH via NADH-dependent educates, which serves as an electron carrier and is located inside the plasma membrane, causing the trapped ions to be reduced into the elemental atom. The nuclei eventually develop into NPs and build up in the cytoplasm or the pre-plasmic space. On the other hand, the stability of NPs is provided by proteins, peptides, and amino acids found inside cells, including cysteine, tyrosine, and tryptophan ( Mohd Yusof et al., 2019 ).

Biosynthesis of NPs by fungi: Because monodisperse nanoparticles with distinct dimensions, various chemical compositions, and sizes may be produced, the biosynthesis of nanoparticles utilizing fungus is frequently employed. Due to the existence of several enzymes in their cells and the ease of handling, fungi are thought to be great candidates for producing metal and metal sulfide nanoparticles ( Mohanpuria et al., 2008 ).

The nanoparticles were created on the surface of the mycelia. After analyzing the results and noting the solution, it was determined that the Ag + ions are initially trapped on the surface of the fungal cells by an electrostatic interaction between gold ions and negatively charged carboxylate groups, which is facilitated by enzymes that are present in the mycelia’s cell wall. Later, the enzymes in the cell wall reduce the silver ions, causing the development of silver nuclei. These nuclei then increase as more Ag ions are reduced and accumulate on them.

The TEM data demonstrate the presence of some silver nanoparticles both on and inside the cytoplasmic membrane. The findings concluded that the Ag ions that permeate through the cell wall were decreased by enzymes found inside the cytoplasm and on the cytoplasmic membrane. Also possible is the diffusion of some silver nanoparticles over the cell wall and eventual cytoplasmic entrapment ( Mukherjee et al., 2001 ; Hulkoti and Taranath, 2014 ).

It was observed that the culture’s age does not affect the shape of the synthesized gold nanoparticles. However, the number of particles decreased when older cells were used. The different pH levels produce a variety of shapes of gold nanoparticles, indicating that pH plays a vital role in determining the shape. The incubation temperature also played an essential role in the accumulation of the gold nanoparticles. It was observed that the particle growth rate was faster at increased temperature levels ( Mukherjee et al., 2001 ; Ahmad et al., 2003 ). The form of the produced gold nanoparticles was shown to be unaffected by the age of the culture. However, when older cells were utilized, the particle count fell. The fact that gold nanoparticles take on various forms at different pH levels suggests that the pH is crucial in determining the shape. The incubation temperature significantly influenced the accumulation of the gold nanoparticles. It was found that higher temperatures caused the particle development rate to accelerate ( Mukherjee et al., 2001 ; Ahmad et al., 2003 ). Verticillium luteoalbum is reported to synthesize gold nanoparticles of 20–40 nm in size ( Erasmus et al., 2014 ). Aspergillus terreus and Penicillium brevicompactum KCCM 60390 based metal NPs are reported for their antimicrobial ( Li G. et al., 2011 ) and cytotoxic activities ( Mishra et al., 2011 ), respectively.

Biosynthesis of NPs using actinomycetes: Actinomycetes have been categorized as prokaryotes since they share significant traits with fungi. They are sometimes referred to as ray fungi ( Mathew et al., 2010 ). Making NPs from actinomycetes is the same as that of fungi ( Sowani et al., 2016 ). Thermomonospora sp., a new species of extremophilic actinomycete, was discovered to produce extracellular, monodispersed, spherical gold nanoparticles with an average size of 8 nm ( Narayanan and Sakthivel, 2010 ). Metal NPs synthesized by Rhodococcus sp. ( Ahmad et al., 2003 ) and Streptomyces sp. Al-Dhabi-87 ( Al-Dhabi et al., 2018 ) are reported for their antimicrobial activities.

Biosynthesis of NPs using algae: Algae have a high concentration of polymeric molecules, and by reducing them, they may hyper-accumulate heavy metal ions and transform them into malleable forms. Algal extracts typically contain pigments, carbohydrates, proteins, minerals, polyunsaturated fatty acids, and other bioactive compounds like antioxidants that are used as stabilizing/capping and reducing agents ( Khanna et al., 2019 ). NPs also have a faster rate of photosynthesis than their biosynthetic counterparts. Live or dead algae are used as model organisms for the environmentally friendly manufacturing process of bio-nanomaterials, such as metallic NPs ( Hasan, 2015 ). Ag and Au are the most extensively researched noble metals to synthesized NPs by algae either intracellularly or extracellularly ( Dahoumane et al., 2017 ). Chlorella vulgaris ( Luangpipat et al., 2011 ), Chlorella pyrenoidosa ( Eroglu et al., 2013 ), Nanochloropsis oculata ( Xia et al., 2013 ), Scenedesmus sp. IMMTCC-25 ( Jena et al., 2014 ) based metal NPs are reported for their potential catalytic ( Luangpipat et al., 2011 ; Eroglu et al., 2013 ) and, antimicrobial ( Eroglu et al., 2013 ; Jena et al., 2014 ) activities along with their use in Li-Ion batteries ( Xia et al., 2013 ).

Intracellular synthesis of NPs using algae: In order to create intracellular NPs, algal biomass must first be gathered and thoroughly cleaned with distilled water. After that, the biomass (living algae) is treated with metallic solutions like AgNO3. The combination is then incubated at a specified pH and a specific temperature for a predetermined time. Finally, it is centrifuged and sonicated to produce the extracted stable NPs ( Uzair et al., 2020 ).

Extracellular synthesis of NPs using algae: Algal biomass is first collected and cleaned with distilled water before being used to synthesize NPs extracellularly ( Uzair et al., 2020 ). The following three techniques are frequently utilized for the subsequent procedure:

(i) A particular amount of time is spent drying the algal biomass (dead algae), after which the dried powder is treated with distilled water and filtered.

(ii) The algal biomass is sonicated with distilled water to get a cell-free extract.

(iii) The resultant product is filtered after the algal biomass has been rinsed with distilled water and incubated for a few hours (8–16 h).

5.2.6.2. Biological synthesis using plant extracts

The substance or active ingredient of the desired quality extracted from plant tissue by treatment for a particular purpose is a plant extract ( Jadoun et al., 2021 ). Plant extracts are combined with a metal salt solution at room temperature to create nanoparticles. Within minutes, the response is finished. This method has been used to create nanoparticles of silver, gold, and many other metals ( Li X. et al., 2011 ). Nanoparticles are biosynthesized using a variety of plants. It is known that the kind of plant extract, its concentration, the concentration of the metal salt, the pH, temperature, and the length of contact time all have an impact on how quickly nanoparticles are produced as well as their number and other properties ( Mittal and Chisti, 2013 ). A leaf extract from Polyalthia longifolia was used to create silver nanoparticles, the average particle size was around 58 nm ( Kumar and Yadav, 2009 ; Kumar et al., 2016 ).

Acacia auriculiformis ( Saini et al., 2016 ), Anisomeles indica ( Govindarajan et al., 2016 ), Azadirachta indica ( Velusamy et al., 2015 ), Bergenia ciliate ( Phull et al., 2016 ), Clitoria ternatea , Solanum nigrum ( Krithiga et al., 2013 ), Coffea arabica ( Dhand et al., 2016 ), Coleus forskohlii ( Naraginti et al., 2016 ), Curculigo orchioides ( Kayalvizhi et al., 2016 ), Digitaria radicosa ( Kalaiyarasu et al., 2016 ), Dioscorea alata ( Pugazhendhi et al., 2016 ), Diospyros paniculata ( Rao et al., 2016 ), Elephantopus scaber ( Kharat and Mendhulkar, 2016 ), Emblica officinalis ( Ramesh et al., 2015 ), Euphorbia antiquorum L. ( Rajkuberan et al., 2017 ), Ficus benghalensis ( Nayak et al., 2016 ), Lantana camara ( Ajitha et al., 2015 ), Cinnamomum zeylanicum ( Soni and Sonam, 2014 ), and Parkia roxburghii ( Paul et al., 2016 ) are the few examples of plants which are reported for the green synthesis of metal NPs (i.e., AgNPs). These were evaluated for their antifilaria activity ( Saini et al., 2016 ), mosquitocidal activity ( Govindarajan et al., 2016 ), antibacterial activity ( Velusamy et al., 2015 ), catalytic activity ( Edison et al., 2016 ), antioxidant activity ( Phull et al., 2016 ), and Cytotoxicity ( Patil et al., 2017 ).

5.2.6.3. Biological synthesis using biomimetic

“Biomimetic synthesis” typically refers to chemical processes that resemble biological synthesis carried out by living things ( Dahoumane et al., 2017 ). In the biomimetic approach, proteins, enzymes, cells, viruses, pollen, and waste biomass are used to synthesize NPs. Two categories are used to classify biomimetic synthesis:

Functional biomimetic synthesis uses various materials and approaches to emulate particular characteristics of natural materials, structures, and systems ( Zan and Wu, 2016 ).

Process biomimetic synthesis is a technique that aims to create different desirable nanomaterials/structures by imitating the synthesis pathways, processes, or procedures of natural chemicals and materials/structures. For instance, several distinctive nano-superstructures (such as satellite structures, dendrimer-like structures, pyramids, cubes, 2D nanoparticle arrays, 3D AuNP tubes, etc.) have been put together in vitro by simulating the protein manufacturing process ( Zan and Wu, 2016 ).

6. Applications of NPs

6.1. applications of nps in environment industry.

Due to their tiny size and distinctive physical and chemical characteristics, NPs appeal to various environmental applications. The properties of nanoparticals and their advantages are illustrated in Figure 4 . The following are some possible NP uses in the environment.

Properties of nanoparticals and their advantages.

6.1.1. Bioremediation

Nanoparticles (NPs) can remove environmental pollutants, such as heavy metals from water or organic contaminants from soil ( Zhuang and Gentry, 2011 ). For example, silver nanoparticles (AgNPs) effectively degrade certain pollutants, such as organic dyes and compounds found in wastewater. Several nanomaterials have been considered for remediation purposes, such as nanoscale zeolites, metal oxides, and carbon nanotubes and fibers ( Zhuang and Gentry, 2011 ). Nanoscale particles used in remediation can access areas that larger particles cannot. They can be coated to facilitate transport and prevent reaction with surrounding soil matrices before reacting with contaminants. One widely used nanomaterial for remediation is Nanoscale zerovalent iron (nZVI). It has been used at several hazardous waste sites to clean up chlorinated solvents that have contaminated groundwater ( Elliott et al., 2013 ). Removing heavy metals such as mercury, lead, thallium, cadmium, and arsenic from natural water has attracted considerable attention because of their adverse effects on environmental and human health. Superparamagnetic iron oxide NPs are an effective sorbent material for this toxic soft material. So, no measurements of engineered NPs in the environment have been available due to the absence of analytical methods able to quantify the trace concentration of NPs ( Elliott et al., 2013 ).

6.1.2. Sensors in environment

Nanotechnology/NPs are already being used to improve water quality and assist in environmental clean-up activities ( Pradeep, 2009 ). Their potential use as environmental sensors to monitor pollutants is also becoming viable NPs can be used as sensors to detect the presence of certain compounds in the environment, such as heavy metals or pollutants. The nano-sensors small size and wide detection range provide great flexibility in practical applications. It has been reported that nanoscale sensors can be used to detect microbial pathogens and biological compounds, such as toxins, in aqueous environments ( Yadav et al., 2010 ). NPS can be designed to selectively bind to specific types of pollutants, allowing them to be detected at low concentrations. For example, gold nanoparticles (AuNPs) have been used as sensors for the detection of mercury in water ( Theron et al., 2010 ).

6.1.3. Catalysts in environment

Nanoparticles (NPs) are used as catalysts in chemical reactions, such as in the production of biofuels or environmental remediation processes, and to catalyze biomass conversion into fuels, such as ethanol or biodiesel. For example, platinum nanoparticles (PtNPs) have been explored for use in the production of biofuels due to their ability to catalyze the conversion of biomass into fuels ( Lam and Luong, 2014 ). PtNPs also showed promising sensing properties; for example, Using Pt NPs, the Hg ions were quantified in the range of 50–500 nM in MilliQ, tap, and groundwater samples, and the limit of quantifications for Hg ions were 16.9, 26, and 47.3 nM. The biogenic PtNPs-based probe proved to be applicable for detecting and quantifying Hg ions ( Kora and Rastogi, 2018 ).

Overall, NPs have significant potential for use in the environment and are being actively researched for a variety of applications.

6.2. Applications of NPs in medicine industry

Nanoparticles (NPs) have unique physical and chemical properties due to their small size, making them attractive for use in various applications, including the medicine industry. Some potential applications of NPs in medicine include:

6.2.1. Drug delivery

Technological interest has been given to AuNPs due to their unique optical properties, ease of synthesis, and chemical stability. The particles can be used in biomedical applications such as cancer treatment ( Sun et al., 2014 ), biological imaging ( Abdulle and Chow, 2019 ), chemical sensing, and drug delivery. Sun et al. (2014) mentioned in detail about two different methods of controlled release of drugs associated with NPs, which were (1) sustained (i.e., diffusion-controlled and erosion-controlled) and (2) stimuli-responsive (i.e., pH-sensitive, enzyme-sensitive, thermoresponsive, and photosensitive). Figure 5 illustrates that how NPs acts as targeted delivery of medicines to treat cancer cells ( Figure 5A ) and therapeutic gene delivery to synthesis proteins of interests in targeted cells ( Figure 5B ). NPs can deliver drugs to specific body areas, allowing for more targeted and effective treatment ( Siddique and Chow, 2020 ). For example AgNPs have been explored for use in drug delivery due to their stability and ability to accumulate in certain types of cancerous tumors ( Siddique and Chow, 2020 ). ZnONPs have also been explored for drug delivery due to their ability to selectively target cancer cells ( Anjum et al., 2021 ). CuNPs have been shown to have antimicrobial properties and are being explored for drug delivery to treat bacterial infections ( Yuan et al., 2018 ). AuNPs have unique optical, electrical, and catalytic properties and are being explored for drug delivery due to their ability to accumulate in certain cancerous tumors. Silver NPs (AgNPs) have been incorporated into wound dressings, bone cement, and implants ( Schröfel et al., 2014 ).

Application of nanoparticles as; targated drug delivery (A) , and therapeutic protein generation in targated cells (B) .

6.2.2. Diagnostics

Nanoparticles (NPs) can be used as imaging agents to help visualize specific body areas. For example, iron oxide nanoparticles (Fe 3 O 4 NPs) have been used as magnetic resonance imaging (MRI) contrast agents to help visualize tissues and organs ( Nguyen et al., 2013 ). AuNPs have unique optical, electrical, and catalytic properties and are being explored for diagnostics due to their ability to accumulate in certain cancerous tumors ( Siddique and Chow, 2020 ).

6.2.3. Tissue engineering

Nanoparticles (NPs) can help stimulate the growth and repair of tissues and organs. For example, titanium dioxide nanoparticles (TiO2 NPs) have been explored for tissue engineering due to their ability to stimulate the growth of bone cells ( Kim et al., 2014 ).

6.2.4. Antimicrobials

Some NPs, such as silver nanoparticles (AgNPs) and copper nanoparticles (CuNPs), have strong antimicrobial properties and are being explored for use in a variety of medical products, such as wound dressings and medical devices ( Hoseinzadeh et al., 2017 ).

Overall, NPs have significant potential for use in the medical industry and are being actively researched for various applications. However, it is essential to carefully consider the potential risks and benefits of using NPs in medicine and ensure their safe and responsible use.

6.3. Applications of NPs in agriculture industry

There are several ways in which nanoparticles (NPs) have the potential to alter the agricultural sector. NPs may be used in agriculture for a variety of reasons, including:

6.3.1. Pesticides and herbicides

Nanoparticles (NPs) can be used to deliver pesticides and herbicides in a targeted manner, reducing the number of chemicals needed and minimizing the potential for environmental contamination ( Khan et al., 2019 ). AgNPs and CuNPs have antimicrobial properties, making them potentially useful for controlling pests and diseases in crops. They can also be used as delivery systems for active ingredients, allowing for more targeted application and reducing the potential for environmental contamination ( Hoseinzadeh et al., 2017 ; Dangi and Verma, 2021 ).

It is important to note that using metal NPs in pesticides and herbicides is still in the early stages of development. More research is needed to understand their potential impacts on human health and the environment ( Dangi and Verma, 2021 ).

6.3.2. Fertilizers and plant growth

Nano fertilizers offer an opportunity for efficiently improving plant mineral nutrition. Some studies have shown that nanomaterials can be more effective than conventional fertilizers, with a controlled release of nutrients increasing the efficiency of plant uptake and potentially reducing adverse environmental outcomes associated with the loss of nutrients in the broader environment. However, other studies have found that nanomaterial has the same or even less effective effectiveness than conventional fertilizers. NPs used to deliver fertilizers to plants more efficiently, reducing the amount of fertilizer needed, and reducing the risk of nutrient runoff ( Kopittke et al., 2019 ).

Ag ( Jaskulski et al., 2022 ), Zn ( Song and Kim, 2020 ), Cu, Au, Al, and Fe ( Kopittke et al., 2019 ) based NPs have been shown to have fertilizing properties and plant growth-promoting properties, and may help provide essential nutrients to plants and improve plant growth and yield. It is important to note that the use of NPs in fertilizers is still in the early stages of development. More research is needed to understand their potential impacts on human health and the environment.

6.3.3. Food safety

Nanoparticles (NPs) can detect and eliminate pathogens in food products, improving food safety, and reducing the risk of foodborne illness ( Zhuang and Gentry, 2011 ).

6.3.4. Water purification

Nanoparticles (NPs) can purify irrigation water, reducing the risk of crop contamination and improving crop yield ( Zhuang and Gentry, 2011 ). Using NPs in agriculture can improve crop yields, reduce agriculture’s environmental impact, and improve food products’ safety and quality.

6.4. Applications of NPs in food industry

Numerous applications for nanoparticles (NPs) in the food sector are possible, including:

6.4.1. Food processing and food preservation/food packaging

Nanoparticles (NPs) can be used to improve the efficiency and performance of food processing operations, such as grinding, mixing, and drying, e.g., AgNPs have been used as a natural antimicrobial agent in food processing operations, helping to prevent the growth of bacteria and other microorganisms ( Dangi and Verma, 2021 ) and also NPs are used to enhance the performance of materials used in food packaging, making them more resistant to pollutants like moisture and gases.

6.4.2. Food fortification

Nanoparticles (NPs) can deliver essential nutrients to food products, such as vitamins and minerals, more efficiently and effectively. e.g., Fe 2 O 3 , and CuNPs have been used to fortify food products with iron, and Cu is an essential nutrient necessary for the metabolism of iron and other nutrients. Iron is an essential nutrient often lacking in many people’s diets, particularly in developing countries ( Kopittke et al., 2019 ).

6.4.3. Sensors

Nanoparticles (NPs) used to improve the sensitivity and specificity of food sensors, allowing them to detect a broader range of substances or signals ( Yadav et al., 2010 ).

Overall, using NPs in the food industry can improve the performance, safety, and nutritional value of a wide range of food products and processes.

6.5. Applications of NPs in electronics industry and automotive industry

In many aspects, nanoparticles (NPs) can transform the electronics sector. NPs may be used in a variety of electrical applications, such as:

6.5.1. Display technologies/storage devices

Nanoparticles (NPs) can be used to improve the performance of displays ( Park and Choi, 2019 ; Bahadur et al., 2021 ; Triana et al., 2022 ), such as LCD and OLED displays, by enhancing the brightness, color, and contrast of the image, such as silver NPs and gold NPs, have been explored for use in LCD and OLED displays as a means of improving the conductivity of the display ( Gwynne, 2020 ). NPs improve the performance and durability of energy storage devices, such as batteries and supercapacitors, by increasing energy density and charging speed. Zinc oxide nanoparticles (ZnO NPs) have the potential to be used in energy storage devices, such as batteries and supercapacitors, due to their ability to store and release energy ( Singh et al., 2011 ).

6.5.2. Data storage

Nanoparticles (NPs) can improve the capacity and speed of data storage devices, such as hard drives and flash drives. Magnetic NPs, such as iron oxide NPs, have been explored for use in data storage devices, such as hard drives, due to their ability to store, and retrieve data using magnetism. These NPs are often composed of a magnetic metal, such as iron, cobalt, or nickel. They can be magnetized and demagnetized, allowing them to store and retrieve data ( Ahmad et al., 2021 ).

Overall, the use of NPs in electronics has the potential to improve the performance and efficiency of a wide range of electronic devices and systems.

Applications of NPs in chemical industry: The chemical industry might be entirely transformed by nanoparticles (NPs) in various ways. The following are potential uses for NPs in the chemical industry ( Salem and Fouda, 2021 ).

6.5.3. Chemical processing/catalysis

Nanoparticles (NPs) can be used as catalysts in chemical reactions, allowing them to be carried out more efficiently and at lower temperatures. Some examples of metal NPs that have been used as catalysts in the chemical industry include: PtNPs have been used as catalysts in a variety of chemical reactions, including fuel cell reactions ( Bhavani et al., 2021 ), hydrogenation reactions, and oxidation reactions ( Lara and Philippot, 2014 ), PdNPs have been used as catalysts in a variety of chemical reactions, including hydrogenation reactions and cross-coupling reactions ( Pérez-Lorenzo, 2012 ), FeNPs have been used as catalysts in a variety of chemical reactions, including hydrolysis reactions ( Jiang and Xu, 2011 ), and oxygen reduction reactions, NiNPs have been used as catalysts in a variety of chemical reactions, including hydrogenation reactions, and hydrolysis reactions ( Salem and Fouda, 2021 ).

6.5.4. Separation and purification

NPs are used to separate and purify chemicals and other substances, such as gases and liquids, by exploiting their size-based properties ( Hollamby et al., 2010 ). Several types of metal nanoparticles (NPs) have been explored for use in separation and purification processes in the chemical industry, including Fe 2 O 3 NPs have been used to separate and purify gases, liquids, and chemicals. They have also been used to remove contaminants from water ( Pradeep, 2009 ; Siddique and Chow, 2020 ). AgNPs have been used to purify water and remove contaminants ( Pradeep, 2009 ), such as bacteria and viruses. They have also been used to remove heavy metals from water and other substances ( Zhuang and Gentry, 2011 ). AuNPs have been used to purify water and remove contaminants, such as bacteria and viruses ( Siddique and Chow, 2020 ). They have also been used to separate and purify gases and liquids ( Zhuang and Gentry, 2011 ). AlNPs have been used to remove contaminants from water and other substances, such as oils and fuels. They have also been used to purify gases ( Zhuang and Gentry, 2011 ).

6.6. Applications of NPs in defense industry

Nanoparticles (NPs) can be used to improve the efficiency and performance of chemical processing operations, such as refining and synthesizing chemicals ( Schröfel et al., 2014 ). Nanoparticles (NPs) have the potential to be used in the defense industry in several ways, including:

6.6.1. Sensors

Nanoparticles (NPs) can improve the sensitivity and specificity of sensors used in defense systems, such as sensors for detecting chemical, biological, or radiological threats ( Zheng et al., 2010 ).

6.6.2. Protective coatings

Nanoparticles (NPs) can improve the performance and durability of protective coatings applied to defense equipment, such as coatings resistant to chemical or biological agents. For example, metal NPs can improve the mechanical properties and durability of the coating, making it more resistant to wear and corrosion. For example, adding Al or Zn based NPs to a polymer coating can improve its corrosion resistance. In contrast, adding Ni or Cr-based NPs can improve their wear resistance ( Rangel-Olivares et al., 2021 ).

6.6.3. Weapons

Nanoparticles (NPs) are used as weapons against viruses, bacteria, etc, ( Ye et al., 2020 ) and as well as in the development of armor and protective materials. There have been some reports of the potential use of NPs in military and defense applications, such as in the development of armor and protective materials. For example, adding nanoparticles, such as ceramic or metal NPs, to polymers or other materials can improve their mechanical properties and make them more resistant to damage. In addition, there have been reports of the use of NPs in developing sensors and detection systems for defense purposes.

6.6.4. Manufacturing

Nanoparticles (NPs) can improve the performance and durability of materials used in defense equipment, such as armor or structural materials. Metal NPs can be used in materials by adding them as a filler or reinforcement in polymers. For example, the addition of metal NPs such as aluminum (Al), copper (Cu), or nickel (Ni) to polymers can improve the mechanical properties, thermal stability, and electrical conductivity of the resulting composite material ( Khan et al., 2019 ).

Metal NPs can also make functional materials, such as catalysts and sensors. For example, metal NPs, such as gold (Au), and platinum (Pt), can be used as catalysts in various chemical reactions due to their high surface area and ability to adsorb reactants ( Zheng et al., 2010 ).

6.6.5. Energy storage

Nanoparticles (NPs) can improve the performance and efficiency of energy storage systems used in defense systems, such as batteries or fuel cells ( Morsi et al., 2022 ). In batteries, nanoparticles can be used as a cathode material to increase the battery’s energy density, rate capability, and cycling stability. For example, lithium cobalt oxide (LiCoO 2 ) nanoparticles have been used as cathode materials in lithium-ion batteries due to their high capacity and good rate performance. In addition, nanoparticles of transition metal oxides, such as iron oxide (Fe 2 O 3 ), and manganese oxide (MnO 2 ), have been used as cathode materials in rechargeable lithium batteries due to their high capacity and good rate performance. In supercapacitors, nanoparticles can be used as the active material in the electrodes to increase the specific surface area, leading to an increase in the device’s capacitance ( Morsi et al., 2022 ). Using NPs in the defense industry can improve defense systems’ performance, efficiency, and safety.

7. Future perspectives

Metal nanoparticles (NPs) have many potential applications in various fields, including electronics, energy storage, catalysis, and medicine. However, there are also several challenges and potential future directions for developing and using metal NPs.

One major challenge is synthesizing and processing metal NPs with precise size and shape control. Many methods for synthesizing metal NPs involve high temperatures and harsh chemical conditions, which can be challenging to scale up for large-scale production. In addition, the size and shape of metal NPs can significantly impact their properties and potential applications, so it is essential to synthesize NPs with precise size and shape control.

Another challenge is the environmental impact of metal NPs. Some metal NPs, such as silver NPs, can be toxic to aquatic life and may have other environmental impacts. There is a need for more research on the environmental effects of metal NPs and the development of more environmentally friendly (Green) synthesis and processing methods.

In terms of future directions, one promising area is the use of metal NPs for energy storage, conversion, and protection of the environment. For example, metal NPs could be used to improve batteries’ performance or develop more efficient solar cells. In addition, metal NPs could be used in catalysis to improve the efficiency of chemical reactions. There is also ongoing research on metal NPs in medicine, including drug delivery and cancer therapy.

Author contributions

KAA: conceptualization, methodology, validation, formal analysis, investigation, writing – original draft, writing – review and editing, and visualization.

Acknowledgments

The author thanks Prof. Dr. Mona M. Sobhy, Department of Reproductive Diseases, Animal Reproduction Research Institute, ARC, Giza, Egypt, and Dr. Omar Hewedy, University of Guelph, Canada, for the critical reading of the manuscript.

Conflict of interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Facet-Dependent Dispersion and Aggregation of Aqueous Hematite Nanoparticles

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Potential and risks of nanotechnology applications in COVID-19-related strategies for pandemic control

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• Published: 09 November 2023
• Volume 25 , article number  229 , ( 2023 )

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• Fatemeh Araste 1 ,
• Astrid Diana Bakker   ORCID: orcid.org/0000-0002-0280-9124 2 &
• Behrouz Zandieh-Doulabi   ORCID: orcid.org/0000-0002-0290-3241 2  

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The ongoing battle against viral infections highlighted so recently by the COVID-19 pandemic demonstrates the need to develop new approaches using nanotechnology in antiviral strategies. Nanoparticles have emerged as promising tools in the fight against viral outbreaks, offering various options for application such as biosensors, vaccine nanoparticles, disinfectants, and functionalized nanoparticles. In this comprehensive review, we evaluate the role of nanoparticles in pandemic control, exploring their potential applications, benefits, and associated risks. We first discuss the importance of nanotechnology in viral outbreak management, particularly in vaccine development. Although lipid nanoparticles play a crucial role in mRNA vaccines, there are concerns about their potential side effects. Although functionalization of protective face masks using metallic nanoparticles has emerged as a sustainable alternative to disposable masks, reducing waste production and enhancing virus filtration, improper disposal of such masks leads to environmental contamination and potential ecological harm. Second, we address the potential adverse effects associated with nanoparticle-based vaccines containing polyethylene glycol and other vaccine components, which trigger autoimmune diseases and alter menstrual cycles. To manage outbreaks effectively, we must minimize such potential risks and environmental impacts. Thus, when developing effective strategies for future pandemic control, it is crucial to understand the advantages and challenges associated with nanoparticle usage.

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Introduction

Throughout the twentieth century, viral infections significantly impacted global health, causing millions of deaths worldwide. To combat these diseases, nanotechnology has emerged as a promising approach in the development of antiviral agents such as biosensors, nanoprobes, virus-like particles (VLPs), and functionalized nanoparticles [ 1 , 2 , 3 ]. The COVID-19 pandemic highlighted the importance of nanotechnology in the battle against viral infections, particularly in the development of vaccines. In turn, ongoing discoveries of new virus variants highlight the importance of being prepared to combat potential future pandemics. Recently, for example, three new COVID-related virus variants were discovered in bats in Laos [ 4 ].

In this review, we evaluate the role of nanoparticles in pandemic control and discuss their potential applications, and also the alarms and risks associated with their use. We also draw on the insights learned from the COVID-19 outbreak regarding the use of nanoparticles in managing viral outbreaks. For instance, although antiviral face masks containing metal nanoparticles were proposed as a more sustainable alternative to disposable masks, since they reduce the amount of non-biodegradable waste material [ 5 ], their improper disposal has contributed to the release of metal nanoparticles into the environment. One recent example was their release into Colombian and Southern Brazilian waters [ 6 , 7 ]. Improper disposal may also cause ecological harm [ 8 ]. A comprehensive understanding of the advantages and risks associated with nanoparticle utilization is therefore essential to their responsible and effective use.

Another significant application of nanoparticles in the fight against COVID-19 is the use of lipid nanoparticle platforms for mRNA vaccines. Although the widespread use of lipid nanoparticles containing mRNA vaccines has contributed significantly to pandemic control [ 9 ], the long-term safety and activity of the vaccine-containing nanoparticles are unclear. Neither have the logistics associated with transport — such as special equipment for storage during transport to remote areas, and the costs this involves — been addressed so far.

Below, we explore the various potentials of nanoparticles in viral outbreak management. More specifically, we discuss the use of functionalized face masks for preventing viral infections, the significance of nanoparticle-based drug delivery systems for antiviral therapeutics, and the role of nanoparticles in diagnostic platforms for rapid and accurate viral detection. We also address the concerns and risks associated with the use of nanoparticles, including their potential ecological impacts and other long-term safety considerations. We highlight the critical role of nanoparticles in tackling viral outbreaks, showcasing their potential applications and stressing the importance of their responsible and ethical use. Through proper consideration of the benefits and risks intricately linked with nanoparticle usage, we hope to ensure the development of effective strategies for future pandemic control.

Nanotechnology applications in SARS-CoV-2 transmission prevention

Functionalization of protective face masks using nanoparticles.

The improper disposal of non-reusable face masks has become an environmental concern, as these masks often contain non-biodegradable materials and pathogenic particles in their filter layer. Over time, the mask weathering caused by factors such as mechanical stress, UV-light, or quartz particles causes the release of microplastics from the masks into the environment [ 10 ].

Surgical masks usually consist of three layers, with a central filter layer. To reduce waste production, this filter layer can be functionalized with metallic nanoparticles composed of silver, zinc, or copper, which interfere with viral reproductive cycles, thereby helping to improve virus filtration over that of ordinary masks [ 11 , 12 , 13 , 14 , 15 ]. Metallic nanoparticles can be used to functionalize face masks through the addition of substances such as photo-sensitizing nanoparticles, which produce reactive oxygen species (ROS) upon exposure to specific wavelengths of light, thereby effectively destroying pathogenic membranes, proteins, and nucleic acids after each mask use [ 16 ]. Plasma-based nanoparticles with photo-thermal efficiency, such as graphene, silver, and gold nanoparticles, are able to self-disinfect when exposed to light, and to absorb any moisture present in the mask [ 12 , 17 ]. Graphene-derivatives add other properties to functionalized face masks, such as resistance to smog, mechanical and abrasion stress, and UV light [ 18 ]. Positively charged polymer nanoparticles have strong virucidal properties that reform and fluidize the lipid content of viral membranes, particularly in lipid-raft areas [ 19 ]. Similarly, biodegradable polysaccharide-based materials successfully combat COVID-19 in facial mask layers, achieving complete decomposition in soil within 4 weeks [ 20 , 21 ].

Various nanotechnology applications in SARS-CoV-2 transmission prevention

As well as functionalizing protective face masks, metallic nanoparticles can be applied in mouthwash and nose rinses, offering new opportunities for combating viral infections. As silver nanoparticles (AgNPs) inhibited SARS-CoV-2 in pre-clinical studies [ 22 , 23 ], they may have potential for wider application. Whereas chemical disinfectants need high concentrations of the active substance, metallic nanoparticles can be used in low concentrations, producing less harmful byproducts and being more effective than standard disinfectants [ 24 ]. Another application of nanotechnology involves spraying nano-sized electrostatic atomized water particles (NEAWPs) onto an electrode on which water molecules have first condensed. This significantly reduces the environmental virus count [ 25 ]. Such use of nanoparticles is particularly important because the excessive use of traditional disinfectants during the pandemic increased levels of quaternary ammonium compounds in water and soil, thereby posing an environmental threat [ 26 ].

Nanoparticles as antiviral therapeutic agents

The main antiviral agents against SARS-CoV-2 infection, i.e., remdesivir, zanamivir, oseltamivir, and abacavir, are specific for HIV and/or influenza, but not for SARS-CoV-2 infections [ 27 , 28 ]. The use of nanoparticles in COVID-19 treatment strategies is promising since the nanoparticles do combat SARS-CoV-2. For example, iron oxide nanoparticles interfere with the S1 subunit of the RBD domain [ 29 ], and amyloid-like proteins from LCB1 and LCB3 sequences of the S protein self-assemble into multivalent spherical nanoparticles, competitively blocking viral interaction with the angiotensin-converting enzyme 2 (ACE2) receptor [ 30 ]. Similarly, linear polyglycerol sulfate and its fullerene-conjugated derivative can block virus entry into host cells [ 31 ]. Biological nanovesicles from human lung spheroid cells that present ACE2, as cell-mimicking nanodecoys, are promising, since they absorb viruses and prevent their attachment to the host cells [ 32 ].

Controlled-release systems of antivirals using nanoparticles

Nanoparticles provide a controlled-release system of antivirals to reduce side effects, increase bioavailability, improve circulation time, or ameliorate delivery of the antivirals [ 33 ]. For example, polymeric nanoparticles made of poly-ε-caprolactone (PCL) or poly-lactic glycolic acid-conjugated-poly-ethylene glycol (PLGA-PEG) decorated with ACE2 ligands successfully encapsulate remdesivir, playing dual antiviral roles through competitive interference with SARS-CoV-2 in ACE2 binding, and through targeted drug delivery to lung cells [ 34 ]. The anti-COVID efficacy of the drug is enhanced by PLGA-lipid hybrid nanoparticles encapsulating fluoxetine hydrochloride [ 35 ]. Table 1 provides information on selected types of nanoparticle that are used against different coronaviruses.

Environmental challenges and urgent action

Adverse effects associated with nanoparticles in personal protective equipment.

Despite some positive aspects of metal nanoparticle usage in personal protective equipment (PPEs) such as masks, potentially adverse effects of metal nanoparticles on ecosystems and their fate in the mask-washing process have not been thoroughly investigated. Their entry into the ecosystem may have unintended consequences.

Due to their high surface-to-volume ratio and reactive surface, nanoparticles are prone to interfere with biological processes. While their environmental impact, particularly that of nanoparticles originating from PPEs, has raised concerns about possible adverse effects on the ecosystem, these effects are not entirely negative. As well as aiding the removal of heavy metals and organic pollutants in wastewater treatment, metal nanoparticles can degrade microplastics and nanoplastics, and produce H 2 O and CO 2 as end-products of degradation [ 8 , 36 , 37 ]. Nonetheless, the prolonged and continuous use of nanoparticles in PPEs leads to the accumulation of toxic levels of degradation products, posing risks to various organisms, and to the entire ecosystem [ 38 ]. In aquatic conditions, metal nanoparticles derived from PPEs can interact with other pollutants. The detrimental effects in organisms range from inflammation to cellular damage that further exacerbate any impact on the environment [ 8 ]. A further problem is the improper disposal of PPEs in landfills, dumpsites, marine environments, or public spaces. This can cause animals to mistakenly recognize such PPE waste as food, resulting in their inadvertent and potentially harmful ingestion.

All in all, urgent action is required to address a range of significant environmental challenges. To promote proper disposal practices and prevent the dissemination of nanoparticles into the environment, specific recycling guidelines tailored to nanotechnology products should be established and enforced [ 19 ]. Before the SARS-CoV-2 pandemic, nanoparticles entered the environment mainly through household usage, industrial waste, or laboratory penetration. However, during the initial stages of the pandemic, when it was believed that the virus could be transmitted through surfaces, the use of antiseptic and disinfectant agents skyrocketed, increasing the release of nanoparticles into the environment. Now, in the post-SARS-CoV-2 period, the main source of nanoparticle pollution is the widespread uncontrolled abandonment of personal protective equipment.

Adverse effects of nanoparticles on plants and microorganisms

During the SARS-CoV-2 pandemic, the worldwide demand for masks reached over 4 billion daily, all while recycling programs for masks were inadequately planned [ 39 ]. Several countries used reusable masks containing carbon nanotubes, and/or silver (Ag), silicon dioxide (SiO 2 ), zinc oxide (ZnO), or nanoparticles titanium dioxide (TiO 2 ). Disposal of nanosilver from these masks was found to pose ecological hazards, inhibiting plant growth and photosynthesis [ 40 ]. Engineered nanoparticles commonly penetrate the roots of plants, resulting in phytotoxicity [ 41 ]. As nanoparticles generate reactive ions interacting with nutrients and inorganic compounds in plants, they cause chlorosis and wilting [ 42 , 43 ]. Small-sized nanoparticles such as TiO 2 pass through protective layers like the cuticle, cell wall, and cell membrane [ 44 ], impairing the growth of seedlings crops, the uptake of minerals, and chlorophyll synthesis [ 45 ]. ZnO nanoparticles reduce chlorophyll production in bulb onions, as well as crop growth and development [ 46 , 47 , 48 ]. Ag nanoparticles increase the activity of antioxidant enzymes, reduce chlorophyll content, and impair photosynthesis in tomatoes [ 49 , 50 ].

Similarly adverse effects of nanoparticles are observed not only in plants, but also in bacteria and aquatic animals [ 51 ]. For example, ZnO-based nanoparticles induce genetic mutations in Caenorhabditis elegans , resulting in offspring toxicity [ 52 , 53 ]. In sea water, TiO 2 nanoparticles released from sunscreens cause severe damage to gill filaments, hampering aquatic animal reproduction [ 54 , 55 ]. Overall, it is therefore clear that the adverse effects of nanoparticles eventually disrupt the food chain for higher organisms.

Adverse effects of nanoparticles on higher organisms

The generation of reactive oxygen species is a biological process. Their excessive generation causes oxidative stress, leading to inflammation, diabetes, cancer, and other degenerative diseases [ 56 , 57 ]. Excessive reactive oxygen species causes free-radical production, lipid peroxidation, genotoxicity, and apoptosis [ 58 ]. Nanoparticles accumulate in various organs and have overall systemic effects [ 59 ]. Some inorganic nanoparticles such as TiO 2 , SiO 2 , ZnO, and Fe 2 O 3 dissolve in the acidic environment of the stomach [ 60 ]. Through absorption into the skin, lungs, and liver [ 61 ], they also impair human health.

Toxicity caused by silver nanoparticles (AgNPs) in vitro depends on the surface coating and the concentration of AGNPs it contains. In vivo, AgNPs enter the bloodstream and accumulate in organs, where they cause cytotoxicity [ 62 ]. The generation of Ag + ions from AgNPs and oxidative stress both lead to apoptosis via translocation of mitochondrial cytochrome C into the cytosol [ 63 ], or to necrosis by reducing sulfhydryl groups [ 64 , 65 ]. Table 2 provides an overview of anti-COVID-19-related cytotoxic effects caused by AgNPs and other types of nanoparticles in vitro and in vivo, and the compendial and noncompendial tests used.

Direct contact with titanium dioxide nanoparticles (TiO 2 NPs) affects skin cells in various ways, for example, by impairing their viability, proliferation, and differentiation [ 66 ]. TiO 2 NPs penetrate into the deep layers of the skin are known to be released in sweat [ 67 , 68 , 69 ]. Inhalation of TiO 2 NPs poses a significant health risk: due to the lower protection provided by the olfactory bulb than by the blood–brain barrier, nano-sized materials can penetrate the brain faster through the olfactory nerve than through systemic injection [ 70 , 71 ].

Being in direct contact with the skin and the air we breathe, protective masks containing Ag and TiO 2 nanoparticles are potentially harmful. The presence of these nanoparticles has been shown to significantly inhibit the growth rate of human osteoblasts, indicating that the adverse effects of the masks are not limited to the skin, inhalation, or brain [ 72 ].

The leaching of Ag + or Cu 2+ ions from metal-impregnated masks has also been linked to potential health risks for humans [ 73 ]. Exposure to these nanoparticles through ingestion, inhalation, or dermal penetration can cause toxicity [ 74 ]. Ingestion is followed by exposure to the complex and harsh condition of the gastrointestinal tract, i.e., pH variations, gastric salts, ions, and enzymes. These interactions modify the composition of nanoparticles, leading to biomolecule adsorption and aggregation [ 75 , 76 , 77 ].

Although nanoparticles have toxic effects on the immune system and are involved in oxidative stress-related disorders, many people attribute these disorders to factors such as air pollution. This has led to proposals for public education on proper disposal of personal protective equipment in government-provided trash containers. Long-term monitoring of coastal waste and citizen initiatives for litter collection in populated areas have also been suggested [ 78 , 79 , 80 ], as has the recycling of carbon powders from masks for use in batteries [ 81 ] or renewable fuels [ 82 ], and the promotion of reusable alternatives and cellulose-fiber textiles. Potential disposal methods also include incineration and optimized pyrolysis [ 82 , 83 ].

The toxicity of metal nanoparticles varies according to the size, surficial coating, and shape of the nanoparticles [ 84 ]. The solubility of AgNPs is inversely proportional to the size of the nanoparticle. Due to increased dissolution and cell penetration efficacy, small nanoparticles exhibit high toxicity, with a strong attachment to DNA also causing DNA damage. Use AgNPs sized more than 20 nm shows less genotoxicity [ 85 , 86 ]. As metal nanoparticles sized less than 100 nm cause increased toxicity in vivo, the recommended ranges lie between 100 and 150 nm [ 87 , 88 ].

Toxicity is also influenced by the type of nanoparticle coating. Coating AgNPs with polyvinylpyrrolidone (PVP) has been found to have a greater toxicity and tissue uptake than citrate coatings, while positively charged polymers such as chitosan enhance the toxicity of AgNPs more than citrate-stabilized particles do. A bovine serum albumin (BSA) coating of gold nanoparticles (AuNPs) also leads to greater toxicity and poorer renal clearance than a glutathione (GSH) coating. On the other hand, coating AuNPs with PEG reduces nanoparticle toxicity and appears to be a suitable coating option [ 85 , 89 , 90 , 91 , 92 ].

Nanoparticles in vaccines and risk assessment

The WHO defines vaccines as pharmaceutical formulations that activate the immune system in order to produce specific antibodies, thereby generating protective immunity against a disease caused by a pathogen [ 93 ]. The conventional vaccines developed since the late eighteenth century rely on the discovery of antibodies in patients who have recovered from infections. To elicit an immune response, these use attenuated or inactivated pathogens and purified pathogen fragments [ 94 ]. Second-generation vaccines are produced using recombinant DNA technology in bacteria or in cell cultures [ 95 ].

Recently, a third generation of vaccines has emerged, which introduces the gene encoding the protective antigen into a host cell. By improving antigen processing and its presentation to antigen-presenting cells (APCs), this enhances the activation of CD4 + and CD8 + cells. This recent advance in vaccine technology holds promise for eliciting protective immune responses against the virus [ 96 ].

To overcome the limitations of conventional vaccines, i.e., attenuated or inactivated viruses, alternative options such as RNA- or DNA-based vaccines have also been sought recently. These new RNA- or DNA-based vaccine production technologies aim both to improve reactivity and efficacy and to reduce the cost of vaccines. They can also be used to effectively treat other diseases, such as cancer. But whereas vaccines need to be delivered to the right places in the body in a suitable form so as to prepare the immune system to combat an invading pathogen effectively, most vaccine molecules are prone to degradation. Due to limited accessibility and poor cell permeation [ 97 ], they may not be recognized efficiently by the immune system. A crucial role in enhancing the effectiveness of vaccines is played by delivery systems based on nanoformulations. By tailoring nanoencapsulation, vaccines can be delivered with precision and stability [ 96 ].

These delivery systems contribute to the in vivo behavior of vaccines in various ways: they protect vaccines from enzymatic degradation, improve their pharmacokinetic properties through surface engineering techniques such as PEGylation, enable active targeting to specific organs or cell types, and engineer controlled release of vaccines [ 93 , 98 , 99 ].

Lipid nanoparticles, self-assembling protein nanoparticles, virus-like particles, liposomes, and cationic nanoemulsion vaccines have been designed against SARS-CoV-2 [ 100 ]. The most prominent vaccines against SARS-CoV-2 are lipid-based nanoparticles (LNPs), which have been designed as drug nanocarriers for nucleic acid delivery [ 101 ]. By protecting fragile and unstable nucleic acids from degradation by nucleases, LNPs can increase the half-life of nucleic acids in the blood circulation. Charge-reversible LNPs contain ionizable lipids, either positively or negatively charged, that allow the LNPs to remain neutrally charged in the bloodstream, effective encapsulation of nucleic acids in the LNPs, and a high degree of endosomal escape of LNPs (Fig.  1 ) [ 102 ].

Schematic illustration of an mRNA-based SARS-CoV-2 lipid nanoparticle vaccine. Different components of the vaccine are visualized, i.e., positively charged lipids, phospholipids, natural lipids, PEGylated lipids, cholesterol, and nucleic acids. This figure is modified from those published in [ 105 ]. PEG, polyethylene glycol

LNPs contain two other main components: cholesterol, a neutral phospholipid, and PEG-lipid, which protects LNPs from phagocytosis and aggregation in the blood circulation and also during manufacturing and storage. In vaccine formulations, the PEG-lipid also ensures that the LNP maintains the desired diameter (200 nm) [ 103 ]. A factor that is crucial to efficient nucleic acid delivery is the complete escape of nucleic acids from the endosomal compartment after LNP internalization. By increasing the diffusibility of PEG-lipids, the addition of distearoylphosphatidylcholine (DSPC) and dioleoylphosphatidylethanolamine (DOPE) lipids to nanoparticles enhances endosomal escape [ 104 ].

To produce viral proteins, leading anti-COVID vaccine developers such as Moderna, Pfizer/BioNTech, CureVac, Walvax, Sanofi, Pasteur, and Entos Pharmaceuticals all use cationic LNPs to deliver mRNA or DNA encapsulated into host cells. Although mRNA vaccines are more prone to instability and functional defects than DNA vaccines, they are preferred due to their higher immunogenicity, their direct translation in the cytosol, and their higher loading potential into LNPs [ 106 , 107 , 108 ]. To achieve the same level of efficiency, self-amplifying mRNA-LNP vaccines such as those developed by Imperial College London and Arcturus/Duke-NUS require ten times less mRNA than mRNA vaccines. However, they have less flexibility in nucleotide modification than their mRNA counterparts [ 102 , 109 ].

Most LNP-derived vaccines currently available induce immune responses against the Spike protein (S protein). Interestingly, the receptor binding (RBD) and N-terminal (NTD) domains of the S protein are targeted by the most potent of the 61 monoclonal antibodies isolated from infected patients [ 110 ]. As anti-NTD antibodies inhibit and anti-RBD antibodies neutralize viral infections [ 111 ], the presentation of one of the virus protein domains is preferred above presentation of the whole protein for optimal immunity against new COVID-19 variants.

Due to the need for expensive low-temperature storage required by the SARS-CoV-2 vaccines currently available, their distribution poses challenges in developing countries. As the mechanical stresses caused by shaking might lead to aggregation and mRNA degradation in LNPs, vaccines also need to be administered promptly after preparation [ 112 , 113 , 114 ]. By enhancing the long-term stability of mRNA-LNPs, freeze-drying offers a solution to both these problems. However, if freeze-drying is to be successful, vaccine structure should not be affected by the lyoprotectants and by temperature stress. A new generation of the Pfizer/BioNTech vaccine is currently being prepared in lyophilized (freeze-dried) form [ 115 ].

Adverse effects associated with SARS-CoV-2 nanoparticle vaccines

Mild to moderate side effects are experienced after vaccinations. Compared to conventional vaccines, Pfizer and Moderna vaccines have been shown to cause more serious allergic reactions, including anaphylaxis. While side effects such as flushing and transient dyspnea were also observed in some of these mRNA vaccines, they were not considered to be allergic reactions [ 116 ]. Similar side effects were reported in earlier clinical safety studies of mRNA vaccines against influenza [ 116 ].

Although the rate of allergic reactions for LNP vaccines containing mRNA cargo is generally around 1.31 (95% CI, 0.90–1.84) per million doses, the number of severe immune reactions may be higher with booster doses [ 117 ]. LNPs induce inflammation, especially in non-adherent cells, due to the higher availability of cell surface receptors than in adherent cells [ 118 , 119 ]. The main suspect for anaphylactic reactions in mRNA vaccines is the coating polymer, PEG, which alters the water solubility of the vaccine-containing nanoparticles [ 120 ]. Although PEG is widely used in cosmetics, food, medication, and pharmaceutical agents, its use in vaccine technology is rare [ 121 ].

Initially, PEG molecules were thought to be safe and biologically inert, but nowadays PEG and PEG-like polymers are not considered to be as safe as initially thought [ 122 ]. An immune response mediated by anti-PEG IgG antibodies may develop in allergic individuals, particularly females [ 123 ]. These antibodies can target the PEG backbone or specifically bind to PEG terminal functional groups [ 124 ]. In the presence of reactive oxygen species, anti-PEG antibodies detrimentally affect the respiratory chain and signal transduction pathways, and also disrupt cell membranes [ 125 ]. In vivo, oxidation of PEG, especially of the PEG low-molecular polymer chains, produces toxic molecules, i.e., glycolic acid and hydroxy acid metabolites [ 126 ]. PEGylated nanoparticles cause pseudoallergic reactions such as complement-activation-related pseudo allergy (CARPA) [ 127 ] and toxic or immunogenic responses, particularly with booster doses. Anaphylactic responses to PEG occur in 2–8 cases per year worldwide, which has led the clinical use of two PEGylated pharmaceuticals to be abandoned [ 128 , 129 , 130 ]. The concentration of PEG in mRNA vaccines is much lower than in PEGylated drugs, and intramuscular administration induces less inflammation [ 131 ]. While anaphylactic reactions are caused not only by PEG, allergic reactions are also caused by vaccine components such as polysorbate 80 in the vaccines developed by AstraZeneca and Johnson [ 132 ]. On the other hand, polysorbate 80 is considered to be safer than PEG [ 128 ]. Figure  2 provides a schematic illustration of the various SARS-CoV-2 vaccines, and Table 3 a summary of the side effects associated with them.

Categorized adverse effects associated with different components of nucleic acid-based lipid nanoparticle vaccines. PEG, excipient, or nucleic-acid-related adverse effects, and adverse effects of known and unknown origin are indicated. Formation of anti-PEG backbone auto-antibodies (blue). PEG, polyethylene glycol

The side effects of PEGylated vaccines and polysorbate-containing vaccines include urticaria, dizziness, diarrhea, wheezing, and tachycardia [ 133 ]. Dermal side effects, such as erythema or swelling, are slightly more common with mRNA vaccines than with adenoviral vaccines (10–15% versus 5–7% of the patients) [ 134 , 135 , 136 ]. Rare side effects of viral vector vaccines include thrombosis and thrombocytopenia. When there is cross-reactivity between PEG and polysorbates, immediate hypersensitivity reactions occur [ 137 , 138 ]. For approximately 6 months, mRNA and adenoviral vaccines can both cause changes in menstrual cycles, such as dysmenorrhea, alterations in frequency, volume, or cessation of bleeding. Women with pre-existing platelet disorders [ 139 ], those taking estrogen-based contraceptives [ 140 ], and those with thrombocytopenia [ 141 ] are all at a higher risk for such changes in their menstrual cycle. Messenger RNA- and viral vaccines affect the menstrual cycle, but the strongest changes are observed with mRNA-LNP vaccines [ 142 , 143 ].

A major concern with the use of nanoparticle vaccines is that they trigger autoimmune diseases. SARS-CoV-2 mRNA-NPs vaccines trigger autoimmune liver diseases, Guillain-Barré syndrome, IgA nephropathy, myocarditis, optical neuromyelitis, autoimmune polyarthritis, Graves’ disease, type 1 diabetes mellitus, and systemic lupus erythematosus [ 144 , 145 , 146 , 147 , 148 , 149 ]. A second concern is the possibility of reverse transcription of mRNA vaccines in liver cells, which has been observed in vitro [ 150 ], although genotoxicity in vivo remains debatable [ 151 ]. A third concern is the phenomenon of original antigenic sin (OAS), which occurs when antibodies from previous infections or vaccinations hinder the neutralization of newly mutated antigens, particularly the omicron antigen variant [ 152 ]. A fourth concern is the concept of antibody-dependent enhancement (ADE), where low antibody titers bind to virus particles without neutralizing them, thereby facilitating virus entry into macrophages and enhancing respiratory disease responses. ADE has been linked to SARS-CoV-2 mRNA-NP vaccines [ 153 ].

A fifth concern has also arisen regarding the cross-reaction of vaccine-induced antibodies against syncytin-1, a placental protein similar to the SARS-CoV-2 spike protein, which activates the immune system and impacts female pregnancy [ 154 ]. Another significant consequence that can arise, mainly in young men, after a second dose of mRNA-based vaccines is myocarditis; this has an incidence of 12.6 cases per million. Sex hormones can contribute to the development of myocarditis [ 155 ], which is not only related to molecular mimicry of S protein, self-antigens, or the formation of autoantibodies, but may also be caused by vaccine adjuvants, activation of “innocent bystanders,” or induction of autoantibodies [ 149 ].

A question we are currently unable to answer is whether the S protein should be replaced by other viral proteins as the immunogenic target to develop vaccines. New generations of vaccines such as spike-trimers and spike-ferritin in liposomes will continue to be based on spike proteins [ 156 , 157 ]. To address and mitigate the side effects of nanoparticle-based vaccines, certain modifications might be considered. PEG chain length and topological configuration affect immunogenicity. Pre-treatment with small amounts of high-molecular-weight PEG reduces anti-PEG reactions, and in animal models, short and hyperbranched PEG polymers, such as poly(oligo-ethylene glycol) methacrylate, exhibit decreased interaction with anti-PEG IgG and IgM antibodies [ 158 ]. To prevent inflammation and side effects, glyceryl monostearate (GMS) should not be included in LNPs [ 118 ]. Promising alternatives for PEG are polyglycerol polyricinoleate, polysarcosine, polyhydroxypropylmethacrylamide, polysulfobetaine, and polycarboxybetaine polymers [ 159 ]. Replacing PEG with polysulfobetaine coating results in higher biological activity of insulin; in nude mice, a dextran coating eliminated toxicity and liver stress of iron oxide nanoparticles [ 160 , 161 ]. Polyesters like polycarbonates and polyphosphoesters might also be viable alternatives to PEG, since they degrade in vivo into non-toxic fragments, and can be easily produced using ring-opening polymerization (ROP) [ 162 ].

More preclinical studies are needed to evaluate vaccines. As two-dimensional in vitro studies may not always completely capture the complex immune environment, and as the phenotype and expression of receptors on cells may be influenced by culture conditions [ 163 ], the prediction of vaccine performance systems might be improved by three-dimensional cell culture systems [ 164 ] and/or standardized in vitro culture systems [ 164 ]. And as small rodents are anatomically different from humans, non-human primates might be more reliable for in vivo studies [ 165 ].

When evaluating nucleic acid vaccines, it is essential to assess not only the quantitative distribution of DNA or mRNA cargo, but also protein expression. This will help to monitor the distribution, retention, and release pattern of the delivered DNA or mRNA, providing a predictive tool for vaccine safety. In addition, valuable insight into the tissue localization of delivered nanoparticles is provided by information on vaccine distribution in lymph nodes, organs, and APCs [ 100 ]. Although a skin-sensitization test is recommended before vaccination with PEG and polysorbate [ 121 , 128 , 166 , 167 ], the number of positive cases in skin tests is considerably lower than the number of sensitive cases after vaccine administration [ 168 ]. Protocols for graded dosing of vaccines have been developed for hypersensitive individuals, such as those with basophil disorders and uncontrolled asthma. Allergic individuals are advised to receive a second dose of a different vaccine, or, in some cases, heterologous prime-boost vaccines are recommended [ 169 , 170 , 171 ]. Finally, in Fig.  3 , we propose several solutions that will minimize the disadvantages associated with nanoparticle use.

Proposed solutions for minimizing the disadvantages associated with nanoparticle usage

Conclusions

The use of nanoparticles in combatting viral infections has proved to represent a promising and valuable approach in the realm of global health. The COVID-19 pandemic underscored the significance of nanotechnology in vaccine development, infection prevention, and therapeutic strategies. By offering innovative solutions — including functionalized face masks, antiviral therapeutics, and diagnostic platforms — nanoparticles have already showcased their potential in pandemic control. However, the potential risks and challenges associated with their use still require attention, particularly in vaccine development.

Existing LNP formulations have played a crucial role in the rapid development of SARS-CoV-2 vaccines. Unfortunately, vaccine-induced immunity against SARS-CoV-2 is of limited duration, and, to enhance vaccine safety, adverse effects such as anaphylaxis and autoimmune reactions call for modifications in nanoparticle design such as after receiving primary doses, individuals with a history of COVID-19 vaccine anaphylaxis should not receive booster doses of the same vaccine.

The development of long-lasting and immunogenic nanoparticle formulations against SARS-CoV-2 is crucial. To prevent nanoparticle aggregation, surface modification of LNPs is also vital. It is also possible that alternative coating materials, such as shorter-length PEG polymers or other synthetic or natural polymers, may help to minimize side effects and enhance vaccine safety.

Whatever their promise in combating viral infections, the main concerns raised by metal nanoparticles involve their entry into the ecosystem. However, they can also aid in wastewater treatment, microplastic degradation, and environmentally friendly H 2 O and CO 2 production. If responsible nanoparticle use is to be ensured, it is imperative to achieve better control of their toxicity through modifications of nanoparticle size, surface coating, and shape, and also to stimulate public education and proper disposal practices for nanoparticle-based personal protective equipment. Although multiple factors determine whether nanoparticles are toxic, very little information is available on their toxicity, which is sometimes related to the specific drug delivery, and/or to the physical characteristics of the nanoparticles (i.e., their size, surface area, charge, shape, and composition). The adverse effects associated with the use of nanoparticles such as LNPs containing PEG (PEGylated LNPs; Fig.  2 ) limit the use of LNPs in clinical applications. PEG is an FDA-approved compound that is used in pharmacochemical and personal care products. A solution to problems involving its toxicity in clinical uses may be provided by LNP modification, such as by replacing PEG with natural polymers.

The lessons learned from the COVID-19 pandemic have shed light on the importance of responsible and ethical nanoparticle use. In the pursuit of future pandemic control and global health protection, it is essential to continue harnessing the potential of nanotechnology while simultaneously remaining cautious and well-informed. By prioritizing the safety of nanoparticle-based products and vaccines, we will be able to ensure that nanotechnology remains a valuable tool in our fight against viral outbreaks, with minimized risks and enhanced benefits for both human health and the environment.

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The authors thank Dr. Jianfeng Jin and Prof. Jenneke Klein-Nulend for their outstanding help in editing the manuscript. Also, we thank David Alexander for his careful reading of the manuscript.

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Fatemeh Araste

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Araste, F., Bakker, A.D. & Zandieh-Doulabi, B. Potential and risks of nanotechnology applications in COVID-19-related strategies for pandemic control. J Nanopart Res 25 , 229 (2023). https://doi.org/10.1007/s11051-023-05867-3

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DOI : https://doi.org/10.1007/s11051-023-05867-3

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