Nanoscale Interaction Mechanisms of Antiviral Activity

Abstract

Nanomaterials have now found applications across all segments of society including but not limited to energy, environment, defense, agriculture, purification, food medicine, diagnostics, and others. The pandemic and the vulnerability of humankind to emerging viruses and other infectious diseases has renewed interest in nanoparticles as a potential new class of antivirals. In fact, a growing body of evidence in the literature suggests nanoparticles may have activity against multiple viruses including HIV, HNV, SARS-CoV-2, HBV, HCV, HSV, RSV, and others. The most described antiviral nanoparticles include copper, alloys, and oxides including zinc oxide (ZnO), titanium oxide, iron oxide, and their composites, nitrides, and other ceramic nanoparticles, as well as gold and silver nanoparticles, and sulfated and nonsulfated polysaccharides and other sulfated polymers including galactan, cellulose, polyethylenimine, chitosan/chitin, and others. Nanoparticles, synthesized via the biological or green method, also have great importance and are under major consideration these days, as their method of synthesis is easy, reliable, cost-effective, efficient, and eco-friendly, and is done using easily available sources such as bacteria, actinomycetes, yeast, fungi, algae, herbs, and plants, in comparison to chemically mediated synthesis. Chemical synthesis is highly expensive and involves toxic solvents, high pressure, energy, and high temperature conversion. Examples of biologically synthesized NPs include iron oxide, Cu and CuO NPs, and platinum and palladium NPs. In contrast to traditional medications, nanomedications have multiple advantages: their small size, increased surface to volume ratio, improved pharmacokinetics, improved biodistribution, and targeted delivery. In terms of antiviral activity, nanoscale interactions represent a unique mode of action. As reviewed here their biomedical application as an antiviral has shown four major mechanisms: (1) direct viral interaction prohibiting the virus from infecting the cell, (2) interaction to receptor or cell surface preventing the virus from entering the host cells, (3) preventing the replication of the virus, or (4) other processing mechanisms which inhibit the spread of virus. Here these pharmacologic mechanisms are reviewed and the challenges for technology translation are discussed in more detail.

SARS-CoV-2 continues to have a significant impact on public health and socioeconomics worldwide. The emergence of SARS-CoV-2 variants characterized by increased infectivity, transmissibility, and immune escape has heightened the need for antiviral countermeasures against the spread of the virus and the development of severe respiratory disease. With this climate in the world, the emergence of monkeypox virus and the reemergence of polio have heightened anxiety and awareness of the vulnerability of humankind to these threats. Nanoparticle compositions are a promising new class of antiviral. Therefore, we review the current state of knowledge of the pharmacologic mechanisms of antiviral nanoparticles. From the literature, nanoparticle compositions that have shown antiviral activity include but are not limited to copper, alloys, and oxides,^1,2 other metal oxides including zinc oxide (ZnO), titanium oxide (TiO),³ iron oxide,³ and others, such as gold³⁻⁸ and silver nanoparticles² and those synthesized via biological means, nitrides, and other ceramic nanoparticles, sulfated and nonsulfated polysaccharides and other sulfated polymers including galactan, cellulose, polyethylenimine, chitosan/chitin, and others.² These nanoparticles or modified polymers have shown activity against a wide variety of viruses including SARS-CoV-2, HIV, herpes simplex virus (HSV), vesicular stomatitis virus (VSV), influenza (H1N1), human norovirus (HNV), hepatitis B (HBV), hepatitis C (HCV), Zika virus, Ebola, poliovirus, and others. Pharmacologic mechanisms include blocking interaction with the receptor and inhibiting penetration, binding to the virus and the viral envelope, release of reactive oxygen (ROS) species, interfering with the viral genome, disruption of the lipid membrane, lipid peroxidation, disulfide bond cleavage, binding amino acids and protein denaturation, and others.

Figure 1 summarizes the various mechanisms by which nanoscale interactions lead to antiviral activity. As shown in Figure 1, there are four primary nanoscale mechanisms of antiviral activity: (1) nanoparticles direct interaction to the virus, as virucidal (2) nanoparticles interaction to receptors, blocking viral entry inside the cells, (3) nanoparticle entry into the cell interfering with viral assembly and processing, or (4) nanoparticle preventing viral replication. These different mechanisms are discussed in more details in the next sections.

Figure 1.

Results: Pharmacologic mechanisms of antiviral activity.

Nanoscale Interaction Mechanisms of Antiviral Activity

Nanoscale Interaction with Virus

Antiviral mechanisms of viruses have been divided into two types: intracellular (treatment) and extracellular (prevention). Some of the types of extracellular prevention methods of nanoscale interaction with viruses include (a) virucidal, where nanoparticles cleave inside the viruses by interacting with the viral surface protein (gp120) in enveloped and unenveloped virus, blocking the fusion, entry, and infectivity;⁹ (b) virus binding, through complex bond formation and electrostatic interaction, causing the inactivation of virus; (c) receptor blocking of the host cells; and (d) nanoparticle delivery of antivirals against viruses.²

Several nanomaterials such as metal nanoparticles and graphene-based nanosheets have natural virucidal effects because of their specific physiochemical properties. Their mechanism of action comprises of a direct interaction with the envelope or capsid proteins of viruses to disrupt structural integrity of virus and inhibiting its infectivity. AgNPs have been found to be effective both outside of cells to block virion entry as well as inside of infected cells to inhibit replication. Copper nanoparticles and their composites usually work by generating ROS and oxidize capsid proteins, inhibiting swine H1N1 influenza virus.¹⁰

Polycations also show antiviral activities by inactivating the influenza virus through adsorption onto the influenza virus surface, damaging the lipidic envelope, and leaking the RNA.² Ag nanoparticles either directly interact with virus particles or prevent their adsorption, including binding, attachment, and penetration into the cell.¹¹

However, the antiviral activity of metal-based nanoparticles is far clearer and well researched, and antiviral activities are shown by undergoing UV photocatalysis, which results in release of reactive oxygen species, damaging the viral biomolecules, or breaking the disulfide bonds within viral glycoproteins, causing the denaturing of viruses.³

Research against HIV-1 virus revealed that AgNPs act as viricidal agents against the virus by inhibiting the binding of the virus to host cells through interaction with gp120 protein of virus envelop.⁹

Copper-based nanoparticles such as CuI NPs generate ROS (reactive oxygen species). These free radicals degrade the hemagglutinin and neuraminidase glycoproteins that influenza uses to bind its host cells. Iron oxides are predicted to directly interact with S1-RBD on the SARS-CoV-2 spike protein, leading to irreversible conformational changes that would prevent viral binding to host cells.³

Nanoscale Interaction to Receptors

There are several mechanisms involved blocking the viruses from entering the host cells through receptors, where their basic purpose is to do the replication of themselves inside the nucleus of the host cell as mentioned in Figure 1. The nanoscale interaction of antiviral nanoparticles prevents the viruses from entering the host cells, either by blocking the receptor site or by altering the structure of the viruses, making them unable to attach properly to the receptor.

Viruses enter host cells through specific receptors present on the host cell membrane using attachment proteins in the viral capsid or glycoproteins embedded in the viral envelope. The mechanism of the interaction that viruses use determines the kind of host cells the virus infects. For example, in the case of bacteriophages, they enter the host cell by keeping their capsid outside the cell and letting their nucleic acid enter inside the cell. Some animal and plant viruses enter host cells through endocytosis. While inside the host cell, RNA viruses such as SARS-CoV-2 use their genomic for the synthesis of viral genomic RNA, and eventually they release new virions, produced in the host cells, out of the host cell.¹²

Attachment of the virus to the host cell is dependent on the specific types of interactions among certain molecules on viruses and host cells. Antibodies can bind to the virus in the extracellular space and thus prevent this attachment to the cell, resulting in reduced infection by the viruses.¹³

A cadmium telluride (Cd)Te quantum dots study reveals that they have the ability to alter the structure of surface proteins of the virus, inhibiting the virus from entering the host cells. Furthermore, the binding of CdTe QDs to the cell membrane receptors themselves also decreased viral numbers.¹²

In the case of the H3N3 influenza virus, where the envelope of the H3N3 influenza virus has two main glycoproteins—hemagglutinin and neuraminidase, the hemagglutinin is the main protein that binds to the host membrane receptor. AgNPs inhibit hemagglutinin through interfering with the disulfide bond present on the molecule and protect the host cell by inhibiting viral genome entry and fusion.⁹

Well-conserved receptors and coreceptors present on the host cells are promising targets for therapeutics that prevent HCV infection. The examples of these target molecules are CD81, SR-B1, and claudin 1 receptors. Usage of small compounds that target glycoproteins in the HCV envelope and thus block viral entry is genotype specific. Usage of nanostructures on these receptors could be an alternative approach in the therapy of HCV infections.¹¹

Different viruses attach to the different receptors of the host cells, for example, JCPyV attaches to host cell α2,6 SA-containing LSTc and requires 5-HT2 receptors for entering the host cell, through clathrin-mediated endocytosis (CME). Adenovirus binds to CAR and then binds to integrins including αvβ3 and αvβ5 to mediate CME. Zika virus utilizes the AXL receptor tyrosine kinase (AXL) through AXL ligand Gas6, which bridges AXL and PtdSer on the viral envelope to mediate viral entry and activate the Type 1 IFN pathway and IFN-stimulated genes (ISGs).⁹

Polypeptides like dextran-propan-1,3-diamine are also the most potent inhibitors of HSV entry, probably via the interaction with cell receptors in host cells.² Unmodified PEI also inhibits the entry of HPV and cytomegalovirus (HCMV) by blocking HS cell receptors.²

Nanoscale Interactions, Preventing the Production of Virion Components

Enveloped human viruses use two basic mechanisms for entry into the cell, involving the fusion of the viral envelope with a cellular membrane to release the nucleocapsid into the cytoplasm. Paramyxoviruses, some of the retroviruses (HIV-1), and herpesviruses enter the cell by the process called direct fusion. The viral envelope becomes incorporated into the plasma membrane of the infected cell, and due to the fact that it still expresses its fusion proteins, infected cells have a tendency to fuse with other uninfected cells. Nonenveloped viruses enter the cell by viropexis. The viral capsid proteins of nonenveloped viruses expose hydrophobic domains resulting in the binding of the virions to the membrane and release of the nucleic acid genome into the cytoplasm. In some cases, the virions may escape the endosomal vesicles by simple stimulation of the lysis of the vesicle. This step is a potential target of antiviral therapy.¹³

Intracellular mechanisms of preventing the virus from doing its replication using the nanoparticles, inside the host cells, are basically related to virus uncoating, nucleic acid and protein synthesis inside the nucleus, virus assembly, and release of virus particles, outside the host cell.¹³ In addition, the major role of antiviral nanoparticles is to prevent this whole process of disassembly inside the host cell.

Retroviruses, influenza viruses, and all the DNA viruses, except the poxviruses, replicate in the nucleus and must move from the cytoplasm to the nucleus. The larger DNA viruses, herpes viruses, and adenoviruses must uncoat to the level of cores before entry into the nucleus, whereas smaller DNA viruses (parvoviruses and the papovaviruses) enter the nucleus intact through the nuclear pores and subsequently uncoat inside. The largest of the human viruses, the poxviruses, accomplish their entire replicative cycle in the cytoplasm of the infected cell.¹³

Nanoparticles such as CeO₂ (cerium oxide) have high binding capacity for nucleic acids in adeno-associated virus, adenovirus, human immunodeficiency virus, and murine leukemia virus and bind to their nucleic materials after their protective capsid is removed for replication, inside the cell.¹⁴

Nanoscale Interactions, Preventing the Virus from Replicating

The major step in every viral infection is the production of virus-specific mRNAs, that is supposed to direct the synthesis of the viral proteins and other structural proteins, enzymes required for genome replication, gene expression, and virus assembly and release. Viral mRNAs are synthesized by the host DNA-dependent RNA polymerase (RNA polymerase II). The (single)-strand RNA viruses (the picornaviruses, the togaviruses, and the coronaviruses) possess positive single-stranded RNA which is used directly in the process of translation immediately after their entry into the cytoplasm of the cell.¹³

Some of the viruses need RNA-dependent RNA polymerase required for synthesis of the new mRNA, since there is no cellular machinery that can use either single- or double-stranded RNA as a template to synthesize mRNA. So, poxviruses and viruses that use an RNA template to make mRNAs must provide their own transcription machinery to produce the viral mRNAs at the beginning of the infection process.¹³

The extent to which viruses use the cell replication machinery usually depends on their protein-coding and also on the size of their genome. The smallest of the DNA viruses, the parvoviruses, are completely dependent on host machinery, meaning that they can replicate only in the dividing cells. To some extent, more complex adenoviruses and herpesviruses, in addition to providing origin-specific proteins, also encode for their own DNA polymerases and other accessory proteins required for DNA replication.¹³

Viruses leave the cell by several mechanisms: via budding, apoptosis, and exocytosis and through induction of the cell lysis. Viruses that leave the cells via budding acquire an envelope around the virion. Prior to budding, the virus incorporates its own receptor onto the surface of the cell, forming an envelope with the viral receptors on it, eventually leading to the demise of the cell. This is also how antiviral responses are able to detect virus-infected cells.¹³

After the disassembly of virus components inside the host cells (either in cytoplasm or nucleus), some of the nanoparticles show their antiviral abilities by preventing the replication of viruses, so they will not be able to multiply their number, and as a result reducing or weakening their infectivity.

Nanoparticles such as chitosan, calcium phosphate, and titanium oxide nanocomposites have all been leveraged for gene silencing and inhibiting influenza viral replication.¹²

Nanoparticles such as AgNPs interfere with the viral replication and inhibit the release of new virus progenies at nontoxic doses 10–25 μg/mL in the size range of 10 nm in a study against Tacaribe virus (new world arenavirus).⁸ Ag nanoparticles can prevent the replication by attaching themselves to the viral genome and also block interaction between various viral and cellular factors responsible for reproduction, contributing to the inhibition of viral replication and the release of progeny virions.⁹ AgNPs capped with mercaptoethanesulfonate at 400 μg/mL completely block HSV-1 infection by inhibiting its replication. AgNPs also inhibit early phase replication of HSV-2 at a nontoxic concentration of 100 μg/mL in VERO cells. However, at the low dose of 6.25 μg/mL, the AgNPs could inhibit the new progeny release, and at a high dose of 100 μg/mL viral replication is inhibited. Furthermore, if Vero cells are coated with polysaccharides, they protect the cells from AgNPs cytotoxic effects. Another research study on herpes simplex virus and human parainfluenza virus type 3 suggested that AgNPs interfere and decrease replication of virus depending upon the size and zeta potential of AgNPs.⁹

Nanoparticles Inhibiting Viral Replication through Immune Modulation

NPs have the ability to initiate both humoral and cell-mediated immune responses because of their unique physicochemical characteristics. Their physical characteristics such as size, shape, and surface charge of the NPs play a vital role in the duration of antigen presentation and dendritic cell (DC)-mediated antigen uptake, promoting cell-mediated immunity.

Nanovaccines are made of specific antigen, conjugated to a nanomaterial and an adjuvant, having the ability to initiate immunogenic response. NPs aid efficient vaccine targeting to the desired cell and its receptors, thereby minimizing side effects in other areas of the body. They increase the duration of antigen–receptor engagement and thus enhance the immune response.

Specific types of NPs are useful in delivering the antigen for specific purposes into the cytoplasm of the target cell. Packaging of antigens within NPs enhances their protection against enzymatic or proteolytic cleavage. NPs also have the ability to pass through the lymphatic drainage system and activate APCs within the lymph nodes.

NPs aid the DC–T cell interaction in order to boost the downstream immune response. They activate dendritic cells and influence the release of pro- and anti-inflammatory cytokines. Antibody production by plasma B cells and activation of lymphocytes and monocytes is also positively influenced by NP-mediated vaccine delivery.

Examples of NPs which have the ability to induce immune responses include Gold NPs inducing M2e-specific IgG serum antibodies to protect against influenza virus. They are also capable of inducing LLO-specific T cell immunity, against Listeria. Polystyrene NPs can induce CD8 T cells, CD4 T cells, and IL-4 against respiratory syncytial virus (RSV).¹⁵

In Vivo Antiviral Activities of Nanoparticles

A great deal of study has focused on the characteristics, composition, antiviral activity, and efficacy of nanoparticles. Although there have been many in vitro studies on antiviral activities of nanoparticles, among them, the in vivo study of nanoparticles stands out the most, as it gives us the idea about how they work inside the body.

NPs coated with MUS are ideal for multivalent binding; gold NPs coated with MUS ligands are the simplest nontoxic particles. Additional NPs selected in the present in vivo study are the particles coated with a 2:1 mixture of MUS and 1-octanethiol (OT), as they are the most biocompatible, soluble, and resistant to protein.

In order to check the inhibitory in vivo activity of MUS:OT-NPs, it was tested in Balb/c mice infected with RSV. Three groups of 5 BALB/c mice were treated at day 0 with 50 μL of PBS, 50 μL of PBS, or MUS:OT-NPs in PBS (50 μL at 200 μg mL^–1). In the latter two cases this was followed, 10 min later, by inoculation with RSV-Luc (10⁴ PFU). After 3 days, luciferase expression in the lungs was analyzed as a measure of the extent of infection. Untreated mice show a clear pulmonary dissemination of RSV infection. By contrast, the luciferase signal from the lungs of the MUS:OT-NPs-treated group was found to be statistically identical with the noise level set by the signal of uninfected mice treated solely with a PBS solution, indicating that MUS:OT-NPs treatment prevented the pulmonary dissemination of the infection.

Moreover, for the purpose of investigating the biodistribution of MUS:OT-NPs, organ homogenates were subjected to inductively coupled mass spectrometry (ICP-MS) to detect the presence of gold only in the lung, and there was no detectable signal from the spleen, liver, or brain. The localization of the MUS:OT-NPs is consistent with their antiviral activity in the lungs.¹⁶

Composition of Nanoparticles

Nanoparticles can be produced from a variety of synthetic and natural ingredients, which may be organic or inorganic. If they are produced through biocompatible materials including lipids, carbohydrates, proteins, and phospholipids, they are easy to use for antiviral purposes because of their advantages, such as high biocompatibility and low toxicity. The components used for the production of nanoparticles play a vital role in their functional performance. For instance, the polarity of the components (polar or nonpolar) determines the type of antiviral agents that can be encapsulated. They also play an important role in the chemical stability of antiviral agents; for example, many proteins have antioxidant properties that can protect chemically labile substances. The composition of nanoparticles is also kept in mind to control the retention and release of antivirals. So, the release of antivirals within the human gut is also based on the composition: starch is degraded in the mouth by amylase, proteins by proteases in the stomach and small intestine, lipids by lipases in the stomach and small intestine, and dietary fibers by bacterial enzymes in the colon.¹⁷

NPs are composed of three layers: (a) the surface layer, which can be functionalized with a variety of small molecules, metal ions, surfactants, and polymers; (b) the shell layer, which is chemically different material from the core; and (c) the core, which usually refers the NP itself.¹⁸

Table 1 summarizes the mechanisms of action, different types of nanoparticles, and the viruses they have been shown to inhibit.

Table 1. Summary of Nanoscale Antiviral Interaction Mechanisms.

Mechanism of Action	Nanoparticles	Viruses	Refs
Virucidal	Cu and its alloys	SARS-CoV-2	(2, 19−24)
	TiO2	Hepatitis C virus (HCV)
	Nitrides (Ceramics)
	Titanium dioxide
	Polycations (polyacrylamide and acrylate based)
	Polyethylenimine-based polycations	Human papillomavirus (HPV), ADV
	Cu and its alloys
	Chitosan/chitin	Ebola
	Sulfated Dextran	Hepatitis B Virus (HBV)
Virus binding and receptor blocking	Metallic NPs	HIV-1	(2, 25−32)
	Ceramic oxide NPs	HSV-1
	Green synthesis using Lampranthus coccineus and Malephora lutea plant extract AgNPs
	Gold (Au)	Respiratory syncytial virus (RSV), influenza A, human papillomavirus (HPV), vesicular stomatitis virus, Measles virus
	Sulfated polysaccharides
	Nonsulfated polysaccharides (alginate)	Hepatitis C virus (HCV), HIV, ZIKA Virus
	Polyanions (nucleic acids)	Ebola
	Polyethylenimine, Polyacrylamide and acrylate-based polycations	HIV
Interact with viral protein, damage viral coating	Magnetic hybrid colloids (AgNPs)	ADV	(9, 3, 2, 8, 33, 34)
	Iron Oxide (Fe3O4)	Influenza A
	Green synthesis using Lampranthus coccineus and Malephora lutea plant extract AgNPs	HSV-1
	Synthetic AgNPs (PVP coated)	HIV-1
ROS generation through photocatalytic reactions driven by UV–vis light, damage viral envelopes, interfere with viral entry and replication,	Titanium dioxide (TiO2)	HSV-1, Influenza A (H1N1), human norovirus-like particles (HNV),	(3, 35−40)
	Copper and Copper oxides (CuO and Cu2O)	Hepatitis B Virus (HBV)
	Zinc oxide (ZnO)
	AgNPs	HIV, poliovirus, Hepatitis B Virus (HBV)
Cytotoxic	Biologically synthesized AgNPs using Seaweed	HSV-1	(9, 41, 42)
Delivery system against viruses	Synthetic, micellar, and liposomal polymers	Hepatitis C virus (HCV)	(2, 43−45)

As summarized a variety of different types of nanoparticle compositions have been shown to exert antiviral activity. The antiviral nanoparticles were produced by chemical or biological methods. In addition to SARS-CoV-2, several different studies have shown effective inhibition of HIV or hepatitis viruses. Influenza and HSV have also been inhibited by zinc and titanium oxide nanoparticles. Taken together the summation of these studies are a powerful indicator of nanoscale interaction mechanisms being central to virus inhibition, by several different mechanisms.

Opportunities and Challenges for Clinical Translation

Comparing the Advantages of Nanoscale Interactions for Antiviral Activity to Traditional Medicine

Figure 2 depicts the advantages of nanoscale interaction antiviral activity over traditional antiviral drugs. Nanomaterials seem to have modified pharmacokinetics, reduced toxicity, more patient compliance, targeted drug delivery, etc., whereas traditional medications are comparatively more toxic, easily metabolized, have shorter half-life, have decreased bioavailability, and show less patient compliance.

Figure 2.

Comparison of tradition medicine and nanotechnology.

Nanomaterials for antiviral applications have several major advantages including decreased drug resistance, modified pharmacokinetics, tissue distribution, as well as increased surface area which can lead to higher payloads for combining drug delivery with other antiviral drugs. The efficacy and effectiveness and improved qualities of nanomaterials across other segments of society may lead to increased patient compliance, as these may be seen as “smart or precision medicine”. Nanoparticles have many physical, chemical, and biological advantages, making them an exciting alternative for regular or traditional drugs. This includes but is not limited to (1) surface charge to facilitate cellular entry across the cellular membrane, (2) ability to anchor targeted particles or microorganisms, increasing their specificity, (3) improved solubility and pharmacokinetic and/or pharmacodynamics properties, allowing their controlled and sustained release, over the desired period of time, (4) reduced toxicity, and (5) ability to perform several functions at the same time, such as their stable structure designed to stimulate the replication of latent virus and deliver an antiviral to the activated cell simultaneously.^47,48 Other types of nanoparticles such as gold and silver are nonphysiological and again for long-term administration may be biopersistent. By contrast, composite nanoparticles containing biometals, such as iron and zinc, may be broken down in cells and tissues which can then reuse and recycle their elements; thus repeated dosing may be possible depending on their formulation and route of administration.

Toxicity of Nanoparticles

Treatment and usage of nanoparticles do not come without challenges, and some of the nanoparticles have their own drawbacks; for example, our lab has shown that copper nanoparticles are quite cytotoxic and can lead to the denaturation and degradation of proteins and RNA (unpublished data). Some types of nanomaterials such as zinc and titanium dioxide are well-known to generate oxidative species which can also lead to some cytotoxicity and local inflammation which may be a cause for concern when given repeatedly. Aluminum oxide NPs can cause genotoxic effects in the form of DNA damage without any mutagenic effects. Chronic exposure to zinc oxide NPs (300 mg/kg) can result in oxidative DNA damage along with altering various enzymes of the liver. Titanium dioxide NPs (5–200 nm) possess toxic effects on immune function, liver, kidney, spleen, myocardium, glucose, and lipids homeostasis in experimental animals.⁴⁶

Scope of Nanoparticles as Antivirals

Depending on the types and mode of administration there may be other limitations. For example, (1) degradation in the gut in the case of oral administration or failure to penetrate the mucus barrier can result in minimal absorbance.⁴⁹ (2) Sometimes nanoparticles have been shown to interact with undesired biological molecules, and this can also lead to activation of inflammatory system, causing their opsonization, uptake by macrophages, and thus reduced plasma half-life.⁵⁰ (3) Occasionally nanoparticles may absorb onto the wrong cells, inducing cell membrane disruption and adverse immunological responses.⁵¹ (4) Still other types develop large dimensions when given intravenously and end up being rapidly cleared in the liver or kidney, therefore limiting their distribution and uptake into other tissues. Coating of nanoparticles onto high exposure surfaces such as personal protective equipment is one way to take advantage of their antiviral activity and limit these concerns. This is a kill-on-contact type of approach avoiding in vivo administration of the nanoparticles. In our experience copper nanoparticles are quite active (unpublished data), and thus composite materials which could limit their absorption in the body but be present for maximal nanoscale interaction may be desirable. Nanocarriers can be coupled with an antibody for the purpose of a targeted therapeutic approach. Nanoparticles can also be delivered via the empty virus capsids, in order to deliver drugs to certain parts of the body. Thus, nanoscale size drug delivery systems may revolutionize the entire drug therapy strategy and can easily be used in the future development of treatment for viral diseases.⁵² Nanotechnology has the potential to bring an evolutionary change in the fields of dentistry, healthcare, and food. They are also capable of bringing significant benefits, such as improved health, better use of natural resources, and reduced environmental pollution.⁵³

Future Directions

While it is clear that nanoscale interaction mechanisms underlie their antiviral activity, the physical chemistry and physical biochemistry of this is poorly understood at present. Detailed spectroscopic and X-ray studies may be necessary to understand nanoscale interactions at a molecular level. From much of what we know now from our studies on zinc oxide or zinc sulfide composites, the nanoparticle interaction to proteins seems to be mediated by cysteine, glutamine, asparagine, and/or aspartate/glutamate residues as studied by Raman spectroscopy (unpublished data). The control of the chemistry at the nanoparticle surface particularly for composites which might include other metals or organic compounds would seem to be key to increasing the specificity of these interactions and thus lowering the nanoparticle concentration needed for virus inhibition.

Summary

This article describes the antiviral activity of nanoparticles, with major focus on describing their mechanisms involved in protecting the host cell from viral infections. Mechanisms include nanoparticles that protect the host cell from getting infected from the virus, by blocking the receptor of host cells, as well as virucidal activity and preventing the virus from entering the nucleus and replicating. This article also compares the traditional drugs and nanotechnology and describes the added benefits of nanotechnology over traditional drugs. There are also various types of viral diseases discussed here for which nanoparticles have been used against, including HIV, HNV, HSV, HBV, HCV, polio, Ebola, and Zika. Detailed explanations of mechanisms involved in protecting the host cells using nanoparticles are summarized here. Apart from the significance of nanoparticles, some of their toxicities are also discussed.

Funding for this project came from NSF 2029579, RAPID - Impact of Coronaviridae lipid, protein and RNA interaction on copper, zinc, and their derivatives coated personal protective equipment surfaces and viral infectivity.

The authors declare no competing financial interest.