Nanotechnology-based antiviral therapeutics

Abstract

The host immune system is highly compromised in case of viral infections and relapses are very common. The capacity of the virus to destroy the host cell by liberating its own DNA or RNA and replicating inside the host cell poses challenges in the development of antiviral therapeutics. In recent years, many new technologies have been explored for diagnosis, prevention, and treatment of viral infections. Nanotechnology has emerged as one of the most promising technologies on account of its ability to deal with viral diseases in an effective manner, addressing the limitations of traditional antiviral medicines. It has not only helped us to overcome problems related to solubility and toxicity of drugs, but also imparted unique properties to drugs, which in turn has increased their potency and selectivity toward viral cells against the host cells. The initial part of the paper focuses on some important proteins of influenza, Ebola, HIV, herpes, Zika, dengue, and corona virus and those of the host cells important for their entry and replication into the host cells. This is followed by different types of nanomaterials which have served as delivery vehicles for the antiviral drugs. It includes various lipid-based, polymer-based, lipid–polymer hybrid–based, carbon-based, inorganic metal–based, surface-modified, and stimuli-sensitive nanomaterials and their application in antiviral therapeutics. The authors also highlight newer promising treatment approaches like nanotraps, nanorobots, nanobubbles, nanofibers, nanodiamonds, nanovaccines, and mathematical modeling for the future. The paper has been updated with the recent developments in nanotechnology-based approaches in view of the ongoing pandemic of COVID-19.

Graphical abstract

Introduction

The world has progressed in many realms, but viral diseases continue to exist and contribute to the mortality of humankind along with its varied socioeconomic manifestations. In recent times, there have been outbreaks of several viral infections caused by corona virus, Nipah virus, Ebola virus, Zika virus, dengue virus, chikungunya virus and different strains of influenza virus—H5N1 (avian flu) and H1N1 and H3N2 (swine flu). Recently, the novel coronavirus (nCoV) has caused severe pandemic claiming lives of approximately 2.1 lakh people so far, with high impact on socioeconomic implications around the world. In 2018, nineteen Nipah virus cases were reported in India, 17 of which resulted in mortality. Since 2001, the fatality rate due to Nipah virus infection has been reported to be between 68 and 100% in India [1]. Major outbreak of Ebola virus disease in West Africa during 2014–2016 claimed 11,315 lives out of 28,616 reported cases. In Australia, in 2019, in the first quarter itself, 27,540 notifications of influenza were received. Although decreased influenza activity is reported for the various continents across the world, different strains of the influenza virus are seen in the various parts of the world with the seasonal influenza A virus predominating [2]. Zika virus transmission has taken over an epidemic proportion in various parts of the world over the past few years. Presently, dengue is seen to afflict South East Asia 17 times more as compared to other viral infections, thus escalating the cost of dengue treatment to about $950 million [3]. Further, in May 2018, around 164,000 dengue incidences had struck globally [4]. Therefore, the economic ramifications associated with viral diseases have been quite high. Various risk factors identified for viral infections include environmental risks including water supply, sanitation facility and climate, life style including smoking and alcoholism, particular geographical area, various medical procedures like blood transfusion, surgery, transmission from vectors, etc. While from among these, a few factors are unavoidable and precautions need to be exercised to avoid them, efforts can be directed toward the others to elicit positive response [5,6,7].

The major challenge that remains in the development of effective antiviral agents is the ability of the virus to multiply in the host cell by liberating its own DNA or RNA. The host’s immune system is highly compromised in case of viral infections and relapses are very common. Also, due to the complexities associated with viruses, treatment is mostly symptomatic and complete eradication of the virus may not be possible. Distinguishing and diagnosing the exact type of viral disease is quite challenging. At times, due to past exposure, viral antibodies present in the host may get activated, rendering it difficult to detect incidental infections [8]. Difficulties faced in the prevention, detection, or treatment are seen as a red signal by the research community, and newer technologies have been explored to overcome the limitations of present therapies. The present review compiles recent advancements made in this direction and opens up new avenues for further research for diagnosis and treatment of viral infections.

General mechanisms of pathogenesis of viral infections

Most of the viral infections are subclinical, where the body’s defense mechanism arrests the course of infection before the clinical symptoms become apparent. Such infections are of great epidemiological significance as they become the means of spread of the virus through populations. Various stages of pathogenesis of viral disease include the following: (i) attachment of virus at point of entry, (ii) penetration into the host cell, (iii) uncoating of the virus, (iv) replication through transcription and translation leading to the synthesis of virus-specific proteins, (v) assembly of naked capsids through nucleocapsid, and (vi) release of virions resulting in further spread of infections [9]. Factors affecting pathogenesis mechanisms include accessibility of tissue to the causative virus, susceptibility of the cell to viral replication, and the resistance of the virus to the host defense mechanisms. The affinity of the virus to infect specific tissue depends on various factors like the presence of virus-specific receptors on the cell, cell transcription factors which enables the cell to recognize viral promoter and enhancer sequences, local pH, temperature, and presence of enzymes which may inactivate the virus [10]. Mechanisms adopted by the virus to cause destruction of the host cell involve blockade of cellular synthesis of macromolecules compromising cellular energy. Integration of the viral genome with the host genome causing mutations in the host genome is the indirect route to cell damage. The infection process is studied on the basis of virulence, virus-dependent factors, virulence genes, amount of inoculum, speed of replication, and degree to which the viral infection spreads [11]. The major issue linked with the study of viral diseases is that it is hard to evaluate the way in which the host defenses would interact with the virus. It may act by preventing the growth of the virus or it may stimulate immunological response in the affected tissue [12]. The basic structures of viruses, certain important proteins of the virus and the host cell which play a significant role in its entry and replication and spread, and currently available FDA-approved treatments and vaccines are presented in Table 1. A pictorial representation of these processes in influenza, dengue, Ebola, Zika virus, herpes infection, and HIV is made in Fig. 1.

Table 1 Important viral and host cell proteins and currently FDA-approved drugs and vaccines for different viral infections

Fig. 1

Pictorial representation of the stages involved in various viral infections

Challenges of antiviral treatment

Continuous efforts in the direction of research on antiviral therapies have improved the quality of life of patients suffering from viral infections. However, the appearance of newer viral infections worldwide and the emergence of multidrug-resistant strains and its transmission have put forward greater challenges to the clinical utility of antiviral therapies.

• (i) Some antiviral drugs are known to interact with regular prescription medicines to give adverse drug–drug interactions [30]. Also, the toxic side effects are common outcomes of long-term treatment module, which may further hinder the patients from following their full medicinal regimen.

• (ii) Many of the antiviral drugs have short half-life, leading to an increase in the frequency of medication and poor patient compliance [31].

• (iii) Development of drug resistance is likely to occur, especially in immunocompromised patients as a result of prolonged drug exposure [32].

• (iv) Low bioavailability as a result of limited solubility or permeability may lead to administration of a higher dose and, consequently, may result in toxic effects [33].

• (v) Few viruses like HIV, Zika virus, and Ebola spread into inaccessible anatomical regions like the CNS, lymphatic system, and synovial fluid often making it difficult for the drugs to reach resulting in reduced therapeutic efficacy [34].

• (vi) Many viral infections remain in the latent stage for a prolonged period and their diagnosis and treatment poses challenges [35].

• (vii) Selectivity of antiviral agents toward the virus over the host cell and identification of the target which is unique to virus life cycle is another challenge in their development [36].

• (viii) Each virus is unique in its structure and function making the development of a broad-spectrum antiviral agent difficult [37].

Application of nanotechnology in antiviral therapeutics

With the advent of nanotechnology, it has been possible to comprehend the cellular mechanisms of the living cells and to develop relevant technologies which facilitate early diagnosis and treatment of various viral infections [38, 39]. Some of its applications consist of drug and gene delivery; use of fluorescent biological labels, detection of proteins, pathogens, and tumors; separation and purification of biological molecules and cells; tissue engineering; MRI contrast heightening; and pharmacokinetic studies [40,143].

Nanospheres

Nanospheres are smaller spherical structures of 10–200 nm diameter, where the drug is uniformly dispersed in the matrix system. This type of nanocarrier shows enhanced size-dependent characteristics, having the capability to prevent the drug from undergoing degradation. In addition, rapid drug clearance is observed due to smaller size. It offers site-specific delivery and the required drug release profiles. Recommended preparation techniques used are solvent evaporation, polymerization solvent displacement techniques, and phase inversion temperature methods [144]. Chitosan nanospheres loaded with acyclovir were synthesized using modified nanoemulsion template method for topical treatment of herpes. The spheres were of the average size of 200 nm and showed better permeation in in vitro skin permeation studies and higher potency against HSV-1 and HSV-2 than the free acyclovir itself [145].

Cyclodextrin-based delivery systems

Cyclodextrins (CDs) are cyclic oligosaccharides made of six to twelve α-d-glucopyranose monomers linked by α1–4 linkages having exceptional hydrophobic interior surfaces and hydrophilic rims with primary and secondary –OH groups. This type of molecular construct entraps the drug in a bucket-shaped cavity, thereby increasing the solubility of the drug and protecting the drug from degradation. Due to this, CDs become preferred delivery system for drugs [146]. The common native or parent cyclodextrins are α-CD, β-CD, and γ-CD comprising of 6, 7, and 8 glycopyranose units and molecular weights of 972, 1135, and 1297 Da, respectively [147]. These CDs have a homogeneous crystalline structure offering numerous advantages like their unique ability to interact with a range of organic and inorganic lipophilic molecules and form inclusion complexes. But their use is restricted due to low solubility of the CDs. Thus, alteration in CDs is being made to make them more suitable for their application in the pharmaceutical industry [148]. β-CD and its derivatives are more widely used than α-CD and γ-CD because of their safety and ease of production. The structural framework of β-CD is attractive with a height of 750–800 pm, external diameter of 1530 pm, internal diameter of 600–680 pm, and cavity volume of 260–265 Å³ [149]. These dimensions make the most ideal hosts for the formation of inclusion complexes. Chemical and enzymatic modifications of macrocycle l in CD derivatives that self-assemble in aqueous solutions provide different shapes of supramolecular nano-assemblies (vesicles, micelles, nanorods, nanospheres, and other kinds of nanoparticles and liquid crystalline structures of 30–500 nm in size depending on the concentration which are very useful for different types of nanodelivery systems) [150]. One of the common problems encountered with antiviral drugs is their poor bioavailability. A similar problem was found with the drug saquanavir. Couvreur and Vauthier formulated CDs loaded with saquanavir using poly(alkylcyanoacrylate) to deal with the issue. This improved solubility in water by 400-fold. Also, it was speculated that saquanavir could now bypass the efflux mechanism of P-gp, preventing its resistance [151]. Similarly, in another study, acyclovir was loaded with CDs using the copolymer such as Eudragit RLPO®, and on evaluation, it was found that intracellular uptake of the drug increased and it had sustained drug release over a period of 24 h [145]. Thus, by utilizing other drugs, CDs with different polymers can be formulated to increase the intracellular concentration of the drug.

Antimicrobial peptides with antiviral activities

Several peptides from natural (includes plants, arthropod venoms, amphibian skin, mammalian tissues) and microbial sources (includes bacteria, algae, and fungi) have been known to possess broad-spectrum antiviral activities. Various mechanisms, either targeting the virus or the host cells have been proposed for their antiviral activities. Some examples include magainin 1 and 2, dermaseptin S4 and temporin B (from frog skin), clavanin (from marine source), latarcin, protegrin (from swine WBCs), cyclotides (from plants), cecropin (from moth), defensins and cathelicidins (from mammals), and poly-γ-glutamic acid (from bacteria) exhibiting potent activity against various viruses like HIV, H1N1, DENV, and HCV [152, 153]. In addition, certain peptides, rationally designed and synthesized depending on the structure of the viral protein and its interaction with the host cell protein, have shown great potential as antiviral agents. Enfuvirtide is the first peptide antiviral drug approved against HIV [154]. Despite various advantages, various hurdles in their production, shorter half-life, and poor bioavailability have limited their use as antiviral agents. Nanotechnology-based solutions have been explored for the delivery of antiviral peptides. Peptide–nanoparticle conjugate systems have been extensively studied. Emileh et al. have reported gold nanoparticle–peptide triazole conjugates to be active against HIV-1 by disrupting the interactions between host receptor proteins and trimeric envelope spike glycoprotein of virus [155]. Recently, Alghrair et al. functionalized silver and gold nanoparticles with an antiviral peptide FluPep and reported increased antiviral potency against influenza A virus [156].

Table 3 compiles a list of polymer-based nanoformulations for antiviral treatment.

Carbon-based nanoformulation

Carbon-based nanoformulations are comprise of carbon nanotubes, graphene oxide nanoparticles, and fullerenes.

Carbon nanotubes

Carbon nanotubes (CNTs) are cylindrical-shaped hollow nanomaterials, viewed as tubes made by rolling up of planar graphene sheets. They can be viewed as coming from the rolling up of a graphene sheet, named as single-walled carbon nanotubes (SWCNTs), or a series of concentric rolled-up graphene sheets termed as multi-walled carbon nanotubes (MWCNTs) [157]. The cylindrical structure is capped with fullerene sheets on one end or both ends. The sp²-hybridized carbon atoms in graphene sheets impart a unique strength to CNTs. In addition, they display other unique characteristics like high aspect ratio, high surface area, cell penetration capacity, and ultralight weight [158]. The chemical vapor deposition (CVD) technique, laser-ablation technique, and electric arc-discharge techniques are commonly employed for the preparation of carbon nanotubes [159]. Though CNTs are widely explored for delivering chemotherapeutic agents at the target site, their overall application in the biomedical field is limited due to pulmonary toxicity and high hydrophobicity [160]. The proposed mechanisms for toxicity are uptaken by macrophages with subsequent generation of ROS and inflammatory mediators. However, functionalized CNTs have shown decreased toxicity and increased biodegradability. CNTs can be decorated with peptides, carbohydrates, and polymers and can be used for targeted therapy, when needed [161]. In one study, Kumar et al. stated about protoporphyrin IX (PPIX)-conjugated multi-walled nanotubes (MWNTs) and its ability to treat influenza using photodynamic therapy. It was found that in the presence of visible light, PPIX-MWNT may indulge in mechanisms like RNA strand breakage, protein oxidation, or protein–RNA cross-linking caused by reactive oxygen species (singlet oxygen and superoxide anion) leading to inactivation of the influenza viral strain. Probing into the inactivation mechanism of carbon nanotubes, they concluded that PPIX-MWNTs can be used for treating any viral infection as it displays nonspecificity in treating viral diseases. Also, PPIX-MWNT can be easily recovered through filtration and reused. Due to its multitarget mechanisms of antiviral action, it was proposed that PPIX-MWNTs have less chances of development of drug resistance [162].

Nanostructures have shown antiviral effect in respiratory syncytial virus, a virus causing severe bronchitis and asthma. The treatment is generally done by combining nanoparticles and gene-silencing technologies. In a novel approach, MWCNTs were functionalized with recombinant dengue virus 3 envelop proteins. This induced significant immune responses in mice [163]. Similarly, conjugation of functionalized CNTs with B and T cell peptide epitopes could generate a multivalent system that was able to induce a strong immune response; thus, CNTs were considered to be good candidates for vaccine delivery [164]. Further, functionalized CNTs were used for the transport of peptides (such as foot-and-mouth virus peptide) for vaccination [165].

Graphene

One of the most promising carbon-based nanomaterials with great potential for antiviral application is graphene. Graphene (G) is a two-dimensional (2-D) planar sheet of hexagonally arranged sp²-hybridized carbon atoms obtained from its three-dimensional (3-D) material of graphite [166]. It is chemically oxidized to graphene oxide (GO) to acquire oxygen bearing functional groups like hydroxyl, epoxide, and carboxylic acids [167]. Graphene-based nanomaterials (GBNs) have high surface area, high loading capacity, and superior mechanical strength which make them attractive candidates for carrying antiviral agents [168]. The oxygen-containing functional groups allow surface functionalization and conjugation strategies and show biocompatibility, reduced toxicity, and good dispersibility [169]. The amphiphilicity of GO makes the incorporation of hydrophilic as well as hydrophobic moieties possible [170]. In addition, these functional groups also provide attachment sites for various biological molecules like proteins, DNA, and RNA [171].

Recently, Pokhrel et al. studied the interactions between graphene and VP40 (viral matrix protein) of Ebola virus using molecular dynamics simulations and graphene pelleting assay. Graphene was found to interact strongly with VP-40 at various interfaces crucial for the formation of the viral matrix. They proposed the use of graphene-based nanoparticle solutions as disinfectant to prevent the Ebola epidemic [172].

In another study, 18 sulfonated magnetic nanoparticles were anchored onto reduced graphene oxide (SMRGO) sheets and used to trap and destroy HSV-1 photothermally, upon their irradiation with near-infrared light. It was found to be effective against 28 viral infections including HSV. It was found that SMRGO has higher entrapment efficiencies in comparison to magnetic nanoparticles due to increased entrap** efficiency, larger surface area, unique sheet-like structure, and outstanding photothermal characteristics shown by graphene [173].

Fullerenes

Fullerenes are among the first discoveries in symmetric carbon nanostructures and have received considerable attention in the case of antiviral research. Fullerenes are comprised fully of carbon atoms forming a nanosized caged hollow sphere. Buckminster fullerene (C60), also known as buckyball, is the most common form of fullerenes with 60 carbon atoms arranged in a spherical structure showing high symmetry [174]. Due to their unique architecture, immense scope of derivatization, free radical scavenging activity, and low toxicity, they are widely studied for drug delivery and antimicrobial and antiviral activities [175].

Fullerenes were found to fit inside the hydrophobic cavity of HIV proteases and inhibit HIV replication [176]. Structure–activity relationship studies revealed trans-position of substitutions and positive charge near the cage to be important for antiviral activity. Fulleropyrolidines with two ammonium groups have been shown to be active against HIV-1 and HIV-2 [177]. Also, fullerene C60 derivatized with two or more solubilizing side chains has been active when tested in CEM culture cells infected with HIV-1 and HIV-2 [178]. Additionally, amino-acid derivatives of fullerene C60 are found to inhibit HIV and HCV replication [179, 180].

Few studies aimed at screening fullerene derivatives for anti-influenza activity. Shoji et al. screened 12 fullerene derivatives for in vitro PA endonuclease inhibition. PA represents the subunit of influenza A RNA polymerase which demonstrates endonuclease activity. It was found that 8 fullerene derivatives demonstrated endonuclease inhibiting potential. In the MDCK cell culture system, these fullerene derivatives inhibited influenza A virus infection and expression of viral nucleoprotein [181].

Few of the studies also aimed at synthesizing anti-influenza fullerenes and evaluating their effectiveness against the influenza virus. Tollas and colleagues also prepared a fullerene conjugate having a thiosialosyl-a(2,6)-galactose disaccharide and evaluated to understand the multimeric interaction of a sialocluster with influenza virus NA and HA. Results revealed that these fullerene derivatives did not target HA but was able to target influenza NA slightly [182].

Table 4 gives an account of various carbon-based nanoformulations for antiviral treatment.

Table 4 Carbon-based nanoformulation

Inorganic-based nanoformulations

Quantum dots (QDs) (2–10 nm) are semiconductor nanocrystals having the shape of dots. They are comprised of a semiconductor core, overcoated by a shell, and a cap leading to improved solubility in aqueous buffers [190]. Fundamental semiconducting character and unique optical and electronic properties are attributed to the presence of the inorganic core consisting of semiconducting materials like silicon, cadmium selenide, cadmium sulfide, or indium arsenide [191]. Quantum dots find interesting applications in biomedical imaging due to its limited light scattering, narrow emission bands, and low tissue penetration. Quantum dots have been widely explored as theranostic platforms for simultaneous sensing, imaging, and therapy [192]. The advantages of quantum dots as a drug carrier system include improved bioavailability and stability of drugs, increased circulation times, active targeting, and localized therapy. In addition to this, QDs can be surface modified with targeting ligands [193, 194]. Yong et al. utilized saquinavir and transferrin (Tf)-conjugated quantum dots for the treatment of HIV. In vitro studies demonstrated that higher concentrations of saquinavir were able to cross the BBB by this method [195].

Metal and metal oxide nanoparticles have been widely explored for their antiviral activity. Among the various metal nanoparticles showing high efficacy are silver and gold, and among the various metal oxides are CuO, SiO₂, TiO₂, and CeO₂. These nanoparticles have shown great efficacy against a broad spectrum of viruses like influenza (H3N2 and H1N1), HBV, HSV, HIV-1, HSV, dengue virus type-2, foot-and-mouth disease virus, and vesicular stomatitis virus [196].

Metal nanoparticles by virtue of their unique shape, size, structure, and local-field enhancement action can interact with viral surface proteins through Kazimir interaction and van der Waals forces causing its inactivation [197]. A variety of surface functionalizations with silane or thiol groups have shown to enhance interaction with biomolecules, affecting viral internalization in cells as well as the release of the drug molecule. Few researchers have also explored further grafting on functionalized metal nanoparticles in order to enhance their efficacy and selectivity [198].

Gold nanoparticles

Gold nanoparticles (AuNPs) are colloids of nanosized particles of gold. AuNPs show special optical properties in the presence of light. When AuNP comes in contact with light, the oscillating electromagnetic field of light triggers coherent oscillation of the free gold electrons [199]. This electron oscillation about the particle surface is responsible for a charge separation with regard to the ionic lattice, leading to a dipole oscillation in the path of the electric field of light. However, when the amplitude of the oscillation becomes maximum at a particular frequency, photons get confined to a small particle size and leads to a special phenomenon known as surface plasmon resonance (SPR) [200]. This SPR boosts all the radiative and nonradiative characteristics of the nanoparticles and, thus, has extensive application in areas of biological imaging, electronics, and materials science [200].

In 2015, Bayo et al. demonstrated that AuNP could enter the cells of various types like lymphocytes, macrophages, and brain microendothelial cells where HIV is known to replicate. Further, they modified raltegravir (RAL) by introducing a thiol group that served as a linker between RAL and AuNP. These particles inhibited HIV replication after penetrating inside infected primary PBMCs (peripheral blood mononuclear cells) exhausted from CD8+. Surprisingly, when the concentration of RAL was increased with the expectation of displaying high antiviral activity, it was found that anti-HIV activity was impaired. The experiment showed positive results when a low concentration of RAL was loaded into AuNP. The authors also performed an experiment using free AuNP and the results proved that it does not have any antiviral activity. So it was just a low concentration of RAL-loaded AuNP which turns it into an active compound having inhibitory action against HIV [201].

Small interfering RNAs (siRNAs) which can target particular viral gene can be employed in the treatment of dengue. However, siRNAs are prone to degradation by serum nucleases and to rapid elimination on account of its small size and anionic character. Paul et al. conjugated siRNAs with AuNPs and found that the complex had enhanced stability and could reduce dengue virus replication and the release of infectious virion in both pre- and post-infection conditions [202].

A breakthrough in the arena of gold nanoparticles was the design and synthesis of long and flexible linkers which mimicked heparan sulfate proteoglycans (HSPG), a target for viral attachment ligand. This allowed effective attachment of the virus to HSPG, generating strong forces that eventually lead to viral deformation. The mechanism was proposed by researchers on the basis of molecular dynamics simulations, electron microscopy images, and virucidal assays. These nanoparticles were nontoxic and effective against a broad range of viruses like HSV, human papilloma virus, respiratory syncytial virus (RSV), dengue, and lentivirus. Additionally, they were found to be active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV [203].

Recently, Halder et al. synthesized highly monodispersed gold nanoparticles, stabilized by gallic acid. Reduction of AuCl₄ using gallic acid was carried out using ultrasound-induced sonication which produced spherical nanoparticles in the range of 7–8 nm. These nanoparticles selectively inhibited HSV with EC50 of 32.3 μM in HSV-1 and 38.6 μM in HSV-2 with better safety profile compared to acyclovir. Prevention of viral cell attachment and penetration was proposed as a mechanism of action of these nanoparticles [204].

Silver nanoparticles

Silver metal possesses intrinsic antimicrobial activity due to its ability to interact with respiratory chain and electron transport chain enzymes and bacterial DNA. It has been extensively studied since ancient times for fighting infections [205]. Silver nanoparticles, on account of its small size and enormous surface area, facilitate rapid dissolution and have shown promising activity against a wide spectrum of viruses [206]. They demonstrate less chances of development of resistance on account of multiplicity of targets they act upon [207]. Nanoparticles of silver possess their own unique properties with regard to chemical stability, catalytic activity, high conductivity, and localized surface plasma resonance enabling researchers to envisage the implication of using AgNPs in disease therapeutics [208].

Galdiero et al. were the first authors to describe the antiviral activity of silver nanoparticles against HIV-1. They studied AgNP with three different surface functionalities: foamy carbon–coated AgNPs, poly(N-vinyl-2-pyrrolidone) (PVP)–coated AgNPs synthesized using glycerol as a reducing agent, and BSA-conjugated AgNPs. They proposed that the interaction between these NPs and the HIV viral surface glycoprotein gp120 was size dependent, as only the NPs in the size range of 1–10 nm were able to bind to the virus. BSA- and PVP-coated nanoparticles demonstrated lower inhibitory activity than silver nanoparticles released from the carbon matrix in in vitro assays on laboratory-adapted HIV-1 strain. AgNPs were shown to block the gp120–CD4 interaction. Additionally, they also were proved to inhibit the post-entry stages of infection by complexing with S and O of thiols and phosphates on amino acids and nucleic acid or directly bind to RNA or DNA, thus reducing the rate of reverse transcription [208]. Baram Pinto et al. synthesized mercaptoethane sulfonate (MES)–functionalized Au and AgNPs against HSV with a strategy to mimic heparan sulfate, present on the cell surface so that they compete for binding of the virus onto the cell. They inhibited HSV-1 infections by blocking the attachment and entry of the virus into the cell [209].

AgNPs have been investigated for their activity against H1N1 influenza virus. ** DNA-based COVID-19 vaccine | Waterloo Stories | University of Waterloo. [cited 2020 Jun 5]. Available from: https://uwaterloo.ca/stories/news/university-waterloo-develo**-dna-based-covid-19-vaccine ." href="/article/10.1007/s13346-020-00818-0#ref-CR297" id="ref-link-section-d59765347e5103">297].

Chinese researchers recently announced their success in develo** a special nanomaterial (nanozyme) that can absorb and deactivate this deadly virus with the efficiency of 96.5 to 99.9% [298].

Novavax, a US-based biotechnology company, has developed a vaccine candidate using its proprietary recombinant protein nanoparticle technology platform to generate antigens derived from the coronavirus spike (S) protein. Novavax expects to utilize its proprietary Matrix-M™ adjuvant with its COVID-19 vaccine candidate to enhance immune responses [299].

Forest business, nanoSeptic, is develo** a mineral nanocrystal-based technique to create a coating material which gets activated by any visible light to cause a strong oxidation reaction to completely breakdown any organic material including the virus. Similarly, a nanotech surface company in Italy has used titanium dioxide and silver ion–based nanoformulations to spray over buildings and surfaces to sanitize them. They claim that with this, the surfaces remain self-sterilized for years [300].

The Iranian government is supporting a manufacturing plant producing 4 million N95 masks per day based on nanofiber technology. They propose that nanofibers produced by electrospinning as perfect filter materials for manufacturing N95 masks. The Czech nanofiber technology firm Respilon Group has incorporated copper oxide into nanofibers to be used for producing mask that has the capability of trap** and destroying the virus. The Advanced Institute of Science and Technology (KAIST), Korea, developed nanofiber-based nanofilters using an insulation block electrospinning process which maintains its filtering efficiency even after 20 washes with ethanol. The orthogonal and unidirectional alignment of nanofibers is claimed to minimize the air pressure toward the filter and maximize filtration efficiency [301].

The World Nano Foundation (WNF) has created a second-generation rapid COVID-19 IgM/IgG antibody assay kit using gold nanoparticles into a testing strip. Also, an MIT spin out startup company has developed strips based on gold nanoparticles which could give the color reaction within 20 min of the start of the test. The strip is coated with antibodies that bind to the specific SARS-CoV2 viral protein and the second antibody is attached to gold nanoparticles. The patient’s sample is placed on the strip, and if it has viral antigen which binds to both these antibodies, a colored spot appears on the strip. Sona Nanotech Inc., a Canada-based company, is develo** a nanorod-based lateral flow test to screen the patient for the nCoV virus, which is expected to produce results within 5–15 min [302].

St. Olavs Hospital in Trondheim used iron oxide nanoparticles coated with silica to extract RNA from a patient’s sample in an attempt to fight the COVID-19 outbreak [303].

PreLynx in their portals have used vapors of a nanopolymer-based sanitizer which gets sprayed on individuals entering through this portal along with scanning of body temperature [304].

Nanoherbal formulations

Herbal drugs and phytoconstituents are considered to be safe and efficacious in comparison with allopathic medicines. Globally, the use of natural medicines is increasing. Principles of nanoscience and technology have been applied to these naturally occurring drugs for the purpose of increasing their bioavailability and achieving targeted delivery [305]. Table 8 gives a compilation of nanotechnology based herbal formulation for antiviral therapy.

Table 8 Nano-herbal formulations for antiviral effect

Overcoming barriers and economization

Despite huge efforts and funds directed toward the development of nanotechnology-based formulations for various indications for the past three decades, there are only about twenty such FDA-approved products available in the market. The majority of these formulations are for cancer and neurological disorders, with liposomes and polymeric nanoparticles being largely used for drug delivery. However, the recent trend in investigational drugs is moving toward micellar systems, nanocrystals, dendrimers, and multicomponent targeted delivery systems and the therapeutic areas addressed are bacterial, fungal, and viral infections [306]. The next decade will witness the rise of nanotechnology platforms for the treatment of microbial infections including viral.

Nanotoxicity as a major limitation

With the rapid advancement of nanoscience in the healthcare sector, its adverse effects and toxicities are parallelly assessed by many scientists. On the virtue of the same reasons that lead to its increased potency, i.e., small size, larger surface area, specific shapes, and surface charges, their interaction at nonspecific target sites also increases [307]. The major mechanism responsible for the toxicity of nanomaterials is considered to be enhanced generation of oxidative stress and inflammatory mediators in various tissues which damage the biological molecules of the cell, namely proteins, lipids, and DNA [

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1. Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, 400056, India

   Malobika Chakravarty & Amisha Vora

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Chakravarty, M., Vora, A. Nanotechnology-based antiviral therapeutics. Drug Deliv. and Transl. Res. 11, 748–787 (2021). https://doi.org/10.1007/s13346-020-00818-0

• Published: 03 August 2020

• Issue Date: June 2021

• DOI: https://doi.org/10.1007/s13346-020-00818-0

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