key: cord-0929623-x0t7jo6n
authors: Delshadi, Rana; Bahrami, Akbar; Mcclements, David Julian; Moore, Matthew D.; Williams, Leonard
title: Development of nanoparticle-delivery systems for antiviral agents: A review
date: 2021-01-13
journal: J Control Release
DOI: 10.1016/j.jconrel.2021.01.017
sha: fc17eb0d383a18cd0899b44596283c01ea7823f8
doc_id: 929623
cord_uid: x0t7jo6n

The COVID-19 pandemic has resulted in unprecedented increases in sickness, death, economic disruption, and social disturbances globally. However, the virus (SARS-CoV-2) that caused this pandemic is only one of many viruses threatening public health. Consequently, it is important to have effective means of preventing viral transmission and reducing its devastating effects on human and animal health. Although many antivirals are already available, their efficacy is often limited because of factors such as poor solubility, low permeability, poor bioavailability, un-targeted release, adverse side effects, and antiviral resistance. Many of these problems can be overcome using advanced antiviral delivery systems constructed using nanotechnology principles. These delivery systems consist of antivirals loaded into nanoparticles, which may be fabricated from either synthetic or natural materials. Nevertheless, there is increasing empHasis on the development of antiviral delivery systems from natural substances, such as lipids, phospholipids, surfactants, proteins, and polysaccharides, due to health and environmental issues. The composition, morphology, dimensions, and interfacial characteristics of nanoparticles can be manipulated to improve the handling, stability, and potency of antivirals. This article outlines the major classes of antivirals, summarizes the challenges currently limiting their efficacy, and highlights how nanoparticles can be used to overcome these challenges. Recent studies on the application of antiviral nanoparticle-based delivery systems are reviewed and future directions are described.

Viral infections pose a serious public health and economic threat globally, as demonstrated by the recent COVID-19 pandemic. It has been estimated that viruses are responsible for around two million deaths per year (Colpitts, Verrier et al. 2015, Rivera and Messaoudi 2015) . Multitudes of different kinds of viruses exist, but only about five thousand of them have currently been identified and characterized. These viruses can enter the human body through a variety of different routes, including the nose, mouth, eyes, and skin (Breitbart and Rohwer 2005) . Human immunodeficiency virus (HIV), norovirus, hepatitis viruses, human papillomavirus (HPV), herpes simplex virus (HSV), and coronaviruses are major pathogenic viruses associated with a large amount of human morbidity and mortality, and antiviral platforms against them will be discussed for the purposes of this review (Evans 2011 , Tseng, Seet et al. 2015 , hepatitis viruses (Acheson and Fiore 2004 , El-Serag 2012 , Liu 2014 , Coppola, De Pascalis et al. 2016 , herpes simplex viruses (HSV) (Brady and Bernstein 2004, Elad, Zadik et al. 2010) , human papillomavirus (HPV) (Carter, Ding et al. 2011 , Liu 2014 , norovirus (Patel, Hall et al. 2009 , Liu 2014 , Kirk, Pires et al. 2015 , Moore, Goulter et al. 2015 , Torgerson, Devleesschauwer et al. 2015 , influenza virus (Blut 2009 , Bertram, Heurich et al. 2012 , Liu 2014 , and the human coronaviruses (Liu 2014 ) (include SARS-CoV-2) (Gonzalez, Gomez-Puertas et al. 2003 , Van Doremalen and Munster 2015 , Sanders, Monogue et al. 2020 .

A broad spectrum of synthetic and natural antiviral substances is available to inhibit viral transmission or treat viral infections. In this section, we highlight some of the most important ones currently in use, as well as the antiviral mechanisms involved.

Different synthetic antivirals can prevent viral infections by inhibition of one or more steps of viral attachment and/or replication (Mazzon and Marsh 2019) (Table. 1). Entry of the virus particle into the host cell is often the first step of infection, which can be prevented by blocking virus receptors on the surface of the host cell membrane or the attachment apparatus on the virus itself (Zhou and Simmons 2012) . For example, enfuvirtide prevents the entry of HIV into host cells. Enfuvirtide (also known as T-20) is a synthetic 36-amino-acid peptide that blocks HIV-1 attachment to the CD4+ host cell membrane by binding to the envelope glycoprotein 41 of HIV-1 in a manner that inhibits the fusion of the virus with the membrane of the CD4+ host cell (Lalezari, Henry et al. 2003) . Maraviroc is another virus entry inhibitor that has been used for the treatment of HIV-1. Maraviroc prevents HIV-1 binding to the CCR5 receptor of the CD4+ cell surface by attaching to CCR5 (Gulick, Lalezari et al. 2008 ).

Journal Pre-proof Protease inhibitors are another type of antiviral agent that have been widely used for treating hepatitis C and HIV (Sulkowski 2003 , Tsantrizos 2008 . These antivirals act upon the proteases that are essential for the replication of viruses. Viral proteases catalyze the cleavage of peptide bonds in cellular proteins or viral polyprotein precursors. Protease inhibitors selectively attach to viral proteases and block proteolytic cleavage of protein precursors, leading to the inhibition of viral replication. For example, indinavir is a popular antiviral to treat HIV and hepatitis B or C (Chastain, Stover et al. 2017, De Leuw and Stephan 2018) .

Polymerase inhibitors are another large group of antiviral agents that play a key role in preventing viral infections (Hayden and Shindo 2019) . Viral genome replication and transcription play a key role in viral replication, which are controlled by viral polymerases. These polymerases are proteins that can often accomplish multiple functions and have a main role in viral genome synthesis. Converting viral genomes into mRNA, which has the capability of translation into viral proteins, is an essential step for the replication of many viruses. The nature of the viral genome and the cellular location have a major effect on genome replication. For example, DNA viruses need a DNA-dependent DNA polymerase, and RNA viruses need an RNA-dependent RNA polymerase to accomplish genome replication (Menéndez-Arias and Andino 2017). Therefore, targeting viral polymerases can drastically disrupt viral replication and reduce the time and/or severity of viral infection.

Acyclovir (ACV) is the first nucleoside analog that selectively prevents replication of herpes simplex virus (HSV) and varicella-zoster virus (VZV). Nucleoside analogs block cellular division or viral replication by impairment of DNA/RNA synthesis or by inhibition of cellular or viral enzymes involved in nucleoside/tide metabolism. ACV can be taken orally, injected, or applied as a cream (Salvaggio and Gnann Jr 2017) . Foscarnet is another polymerase inhibitor that has been used for the treatment of herpesviruses, by direct inhibition of viral DNA polymerase through blocking the release of pyrophosphate from the terminal nucleoside triphosphate when added onto the growing DNA chain J o u r n a l P r e -p r o o f Journal Pre-proof (Andrei, De Clercq et al. 2009 ). It can be taken through intravenous injection or infusion. Abacavir is an oral antiviral that treats HIV by inhibiting viral replication due to nucleoside reverse transcriptase inhibition (Hervey and Perry 2000) . Lamivudine is an oral antiviral used to treat HIV and hepatitis B, which inhibits viruses by phosphorylating active metabolites that compete for incorporation into viral DNA (Jarvis and Faulds 1999) . Adefovir is an antiviral used to treat hepatitis B, which prevents viral replication by blocking a reverse transcriptase (Dando and Plosker 2003) . Telbivudine is another oral antiviral used to treat hepatitis B that inhibits a reverse transcriptase, which has been reported to be more effective than lamivudine and adefovir (McKeage and Keam 2010) . Tentecavir is another antiviral used for the treatment of HIV and hepatitis B, which inhibits viral replication by preventing DNA replication, reverse transcription, and transcription (Robinson, Scott et al. 2006) . Ribavirin is an effective antiviral against hepatitis C, human orthopneumovirus, and viral hemorrhagic fevers, due to its ability to inhibit nucleosides. It can be administered orally or through inhalation (Glue 1999) .

Interferons (IFNs) (a family of cytokines) are released by host cells when they are attacked by viruses. IFNs are a significant part of the innate immune response and defense against many viral infections. Currently, INFs have been investigated for therapeutic potential against various viruses, especially the hepatitis C virus. INFs are classified into three major types (I, II and III) based on the receptor complex they signal through. Type I IFNs attach to a particular receptor complex on the cell surface known as the IFN-α/β receptor (IFNAR). When they are released, they attach to specific receptors on the target cells, which causes protein expression to inhibit the virus producing and replicating its RNA and DNA. Type I INFs are critical for providing a strong general immune response against multiple viral infections. Type II IFNs are activated by and are released by cytotoxic T cells and T helper cells. They attach to the IFNγ receptor (IFNGR) complex and induce a wide immune response to pathogens. Type III IFNs include three IFNλ gene products that signal through receptors containing IFNLR1 and IL-10R2 (Sadler and Williams 2008) . 

Antiviral drugs based on natural compounds have attracted considerable attention from researchers because of their low toxicity, low cost, low side effects, and reduced likelihood of promoting antiviral resistance (Antonio, Wiedemann et al. 2020) . Several bioactive compounds have been found to have activity against viruses, including flavonoids, terpenoids, limonoids, organosulfur compounds, sulfides, polyphenolics, lignans, saponins, coumarins, chlorophyllins, alkaloids, furyl compounds, thiophenes, polyines, proteins, and peptides (Naithani, Huma et al. 2008) . The antiviral activity of these compounds has been attributed to various mechanisms of action, including antioxidant activities, inhibition of DNA and RNA synthesis, and prevention of viral particle entry (Naithani, Huma et al. 2008 , Antonio, Wiedemann et al. 2020 (Pevear, Tull et al. 1999 , Lalezari, Henry et al. 2003 Saquinavir, Ritonavir, Indinavir Protease inhibitors HIV and hepatitis B or C (Ramanathan, Jiang et al. 2016 (Glue 1999 , Jarvis and Faulds 1999 , Hervey and Perry 2000 , Dando and Plosker 2003 , Kearney, Flaherty et al. 2004 , Robinson, Scott et al. 2006 , McKeage and Keam 2010 , Meng, Agrahari et al. 2016 , Joshy, Snigdha et al. 2017 ) Interferons

Cell defense protein activated

Hepatitis B or C (Kakimi, Lane et al. 2001) J o u r n a l P r e -p r o o f against a broad group of viruses including HIV, HSV, HBV, HCV, and influenza (Sohail, Rasul et al. 2011 , Zorofchian Moghadamtousi, Abdul Kadir et al. 2014 .

Essential oils are non-polar substances found in many plants, particularly herbs and spices (Rao, Chen et al. 2019) . These compounds are commonly used as flavoring agents in foods, as well as for their antimicrobial properties. Essential oils are mainly composed of volatile compounds, including monoterpenes (e.g., limonene, α-pinene, P-cymene, and sabinene), phenylpropanoids (e.g., cinnamaldehyde, vanillin, eugenol, and safrole), and monoterpenoids (e.g., thymol, citronellal, carvone, carvacrol, and borneol) (Pandey, Kumar et al. 2017) . Many essential oils have been shown to possess antiviral activity against a variety of enveloped and nonenveloped viruses such as HSV, influenza, adenovirus type 3, Junin virus, poliovirus, norovirus, and coxsackie virus B1 (Table 2) . (Ibrahim, El-Hawary et al. 2015) Carvacrol, p-cymene, γ-terpinene, and β-caryophyllene Murine norovirus (El Moussaoui, Sanchez et al. 2013) Thymol, carvacrol, p-cymene, β-caryophyllene, γ-terpinene, α-zingiberene, camphene, β-sesquiphellandrene, αrcurcumene, β-phellandrene, and β-bisabolene HSV-2 (Koch, Reichling et al. 2008) Thymol, p-cymene, γ-terpinene, and (E)-Cinnamaldehyde Influenza A virus subtype H1N1 (Setzer 2016 ) (Hayashi, Imanishi et al. 2007) Camphor, limonene, p-mentha-1, 8-diene, α-pinene, γterpinene , germacrene D, β-caryophyllene, calamine, leptospermone, flavesone, viridiflorene, isoleptospermone, geranial, menthol, menthone, and isomenthone HSV-1 and HSV-2 (Brand, Roa-Linares et al. 2016 ) (Reichling, Koch et al. 2005 ) (Schnitzler, Schuhmacher et al. 2008 ) (Schuhmacher, Reichling et al. 2003) Patchoulol, δ-guaieno; gurjunene-α, α-guaiene, aromadendrene, and β-patchoulene Influenza A (H2N2) virus (Wu, Ju et al. 2013 ) (Wu, Li et al. 2011) treatments to fight viral infections or their symptoms (drugs). In the latter case, they may be administered through oral, injection, skin, or ocular routes depending on the nature of the formulation and the intended target.

When antivirals are taken orally, they have to pass through the gastrointestinal tract to reach the small intestine where they are usually absorbed and transported to the systemic circulation (Yáñez, Wang et al. 2011 ). There are numerous factors that may impact the bioavailability (B A ) of ingested antivirals, i.e., the fraction that actually reaches the systemic circulation (McClements, Li et al. 2015) :

Here, B* is the bioaccessibility of the antiviral, i.e., the fraction present in the intestinal fluids that is in a form that can be absorbed. S* is the stability of the antiviral, i.e., the fraction that is stable to chemical or enzymatic transformation. A* is the absorption of the antiviral, i.e., the fraction in the intestine that is taken up by the body.

Some antiviral agents are highly hydrophobic molecules with a low water-solubility (such as essential oils and some phytochemicals). As a result, they may not fully dissolve in the gastrointestinal fluids so they are not fully bioaccessible. The bioaccessibility of hydrophobic antivirals can be increased by ingesting them with digestible lipids, such as triglyceride oils (McClements, Li et al. 2015) . Triglycerides are hydrolyzed by gastric and pancreatic lipase in the stomach and small intestine, leading to the formation of free fatty acids (FFAs) and monoglycerides (MGs). The FFAs and MGs interact with bile salts and phospholipids in the intestinal fluids to form mixed micelles, which are small colloidal particles (micelles and vesicles) capable of solubilizing hydrophobic substances. The mixed micelles can then transport the hydrophobic substances to the epithelium cells where they can be J o u r n a l P r e -p r o o f absorbed. Consequently, it may be important to deliver hydrophobic antimicrobials intended for oral ingestion within digestible lipid particles, so as to increase their bioavailability.

Some antivirals may chemically degrade during storage or be damaged by the harsh conditions inside the human GIT, which decreases the concentration of active antivirals reaching the systemic circulation (Galasso, Boucher et al. 2002) . For instance, peptide-based antimicrobials may be hydrolyzed by proteases in the stomach and small intestine. This problem can be overcome by taking a higher oral dose of the antiviral agent, but this approach can lead to undesirable side effects (Liu, Yang et al. 2016 . For this reason, storage and gastrointestinal stability should be considered when designing effective antivirals intended for oral administration, which again may be enhanced by encapsulating the antimicrobials in nanoparticles.

Finally, some antiviral drugs have poor absorption in the gastrointestinal tract because the mucus layer or epithelium cells act as a biological barrier to their uptake (Galasso, Boucher et al. 2002) . For instance, antivirals with high molecular weights typically have low permeability through the intestinal epithelial layer, which affects the permeation and transcellular absorption of antimicrobials by passive diffusion (Adesina and Akala 2015) . The intestinal epithelium is covered by a thick mucus layer and consists of various different kinds of cells, including Paneth cells, enterocytes, goblet cells, M cells, and endocrine cells, which can decrease the uptake of antivirals (Goto and Kiyono 2012) .

problem can be overcome by encapsulating the antiviral drugs in specially-designed particles that "hide" them from the MPS, thereby prolonging their circulation (Drevets, Leenen et al. 2004 , Bhavsar, Guttman et al. 2007 , Muppidi, Wang et al. 2011 . In general, the composition, size, and surface chemistry of the nanoparticles used in antiviral delivery systems must be carefully controlled to ensure that they exhibit their strong antiviral activity after injection, without causing adverse side effects. For instance, it has been reported that under normal flow conditions within blood vessels, the tendency for particles to stick to the endothelial cell surfaces increases as their size increases, which may be important for the uptake of antivirals into the body (Blanco, Shen et al. 2015) . Moreover, the same authors reported that cationic particles tend to get rapidly opsonized and removed from the systemic circulation, whereas neutral particles tend to have prolonged circulation times. Consequently, it may be better to encapsulate antivirals in neutral nanoparticles so as to extend their lifetime in the body.

The skin is the largest organ in the human body and is a popular site for antiviral administration because of its accessibility and ease of application. Some major antivirals are administered as topical formulations through the skin, including acyclovir (Shishu 2009 ). In this case, the antiviral formulation should fuse with the skin lipids and then penetrate into the underlying tissues. The penetration of free antiviral drugs into skin lipids is typically not high, leading to a reduction in their activity (Park and Han 2002) . For this reason, there has been interest in encapsulating antiviral drugs into delivery systems to increase their bioavailability. However, various factors have to be considered for achieving a potent transdermal delivery system for antivirals, such as ensuring that the drug is absorbed into the systemic circulation and reaches a therapeutically active plasma level (Prausnitz, Elias et al. 2012) . The epidermis layer of the skin is designed to protect the body from the loss of water and the penetration of harmful materials, and can therefore act as an effective barrier against drug absorption. The pure forms of many antiviral agents cannot rapidly penetrate through the skin, which J o u r n a l P r e -p r o o f leads to a low active plasma level and antiviral activity (Vavrova, Zbytovska et al. 2005, Williams and Barry 2012). This problem can be overcome by designing antiviral delivery systems that contain carrier particles with dimensions and surface features that promote their penetration and absorbance.

The human eye is a spheroidal organ of about 24 mm in diameter, which consists of anterior and posterior parts (Singh, Logan et al. 2006 ). These parts prevent Conversely, the stroma, which is partly assembled from hydrophilic collagen molecules, acts as a barrier against hydrophobic antivirals (Prausnitz and Noonan 1998) . The blood-retina and bloodaqueous barriers also reduce drug penetration into the intraocular chamber (Cunha-Vaz 1979 , Furuichi, Chiba et al. 2001 . Moreover, there are various other barriers that limit the topical administration of antivirals via the ocular route, including blinking, tear turnover, tear film, solution drainage, lacrimation, and clearance mechanisms on the corneal surface (Gipson and Argueso 2003) . The presence of these different barriers reduces the amount of antivirals reaching the retina and vitreous J o u r n a l P r e -p r o o f body. Consequently, advanced antiviral delivery systems are needed to overcome these barriers and improve the efficiency of ocular administration.

After entering the systemic circulation, there may be additional biological barriers that inhibit the ability of antivirals reaching their target tissues. In particular, the blood-brain barrier (BBB) and bloodtestis barrier (BTB) decrease the penetration of antivirals into the brain and central nervous system, respectively Mruk 2012, Gray, Roche et al. 2014 ). The BBB is a highly selective semipermeable border of endothelial cells, which effectively separates the systemic circulation from the brain parenchyma and extracellular spaces (Daneman and Prat 2015) . The endothelial cells are tightly connected to one another, which inhibits transportation of compounds through the cell membranes. Hydrophilic antivirals cannot easily pass through these membranes because of the lipid domains they contain (Chow and Gu 2015) . Increasing the lipid solubility of antivirals can enhance their penetration through cell membranes, but this can cause a greater tissue burden and higher efflux of the antivirals (Brewster and Bodor 1994) . The BTB normally protects the developing germ cells from damage from chemical interactions and immunological effects, but it can also provide a sanctuary for the HIV virus during antiretroviral therapy (Mruk, Su et al. 2011) .

It should also be noted that prolonged use of antivirals, especially in chronic diseases, leads to the development of antiviral resistance, which can reduce their efficiency (Kim and Read 2010, Lembo, Donalisio et al. 2018) . Consequently, it is important to have a range of different antiviral agents that work by different mechanisms to tackle this problem.

As mentioned in the last section, there are several routes available for delivering antivirals, each with its own specific biological barriers that can decrease the effectiveness of antivirals. Nanoparticlebased delivery systems have considerable potential to overcome a number of these barriers and J o u r n a l P r e -p r o o f therefore increase the efficacy of antivirals (Kosaraju 2005 , Bahrami, Delshadi et al. 2020 . In general, an effective antiviral delivery system should have a number of features:

(i) It should be able to encapsulate an appropriate concentration of the antiviral agent to achieve the desired goal, i.e., enough to prevent or treat viral infection without causing undesirable side-effects or toxicity;

(ii) It should be in a physical form that is suitable for the chosen delivery route, e.g., a low viscosity fluid (injection or oral), a viscous fluid or gel (transdermal or oral), or a powder, capsule or pill (oral);

(iii) It should retain the antiviral agent and protect it from degradation during storage and transport through the body until it reaches the intended site of action;

(iv) In the case of oral ingestion or topical application, it should deliver the antiviral agent in a form that is bioavailable, i.e., a high fraction reaches the systemic circulation;

(v) In some cases, it may be advantageous to have a targeted or controlled release of the antiviral agent.

In general, nanoparticles can be designed that can encapsulate antivirals so as to achieve many of the requirements just outlined.

Nanoparticle-based delivery systems have considerable versatility for the encapsulation, protection, and release of antiviral agents . Their properties can be manipulated in a variety of different ways so as to tune their functionality for particular applications. In this section, an overview of the various physicochemical and structural properties of nanoparticles is given:

 Composition: Nanoparticles can be fabricated from a variety of synthetic and natural ingredients, which may be organic or inorganic. In this article, we mainly focus on the creation of antiviral delivery systems from biocompatible materials including lipids, carbohydrates, J o u r n a l P r e -p r o o f proteins, phospholipids and surfactants, since these have advantages in terms of their high biocompatibility and low toxicity. The nature of the components used to construct the nanoparticles impacts their functional performance. For instance, the polarity of the components used (polar or non-polar) determines the type of antiviral agents that can be encapsulated. They also impact the chemical stability of antiviral agents, e.g., many proteins have antioxidant properties that can protect chemically labile substances. In addition, nanoparticle composition can be selected to control the retention and release of antivirals. For instance, the location that antivirals are released within the human gut after oral ingestion depends on the nature of the particle matrix: 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 (Zhang, Zhang et al. 2015 , McClements 2017 .

 Particle size: Strictly, the definition of a nanoparticle is a particle that has at least one major dimension that is less than 100 nm. In practice, the term is often used more loosely to apply to any particles that have dimensions within the nanometer range, i.e., 1 to 1000 nm (Bahrami, Delshadi et al. 2019) . When particles are in the nanometer range they often have different functional properties than larger particles. For instance, small nanoparticles may appear transparent because of weak light scattering, they may have strong resistance to gravitational separation because of the increased importance of Brownian motion, they may have higher chemical reactivity because of their high specific surface area, and they may be able to can be used to tune the electrical properties of surfaces. In some cases, it is possible to locate targeting molecules on the surfaces of nanoparticles so that they will become attached to viruses or specific tissues within the human body.

Many different kinds of nanoparticle delivery systems can be fabricated from pharmaceutical and/or food grade ingredients, including microemulsions, nanoliposomes, nanoemulsions, solid lipid nanoparticles, biopolymer nanoparticles, and biopolymer nanogels (Figure 1 ). In general, nanoparticles can be produced using two different approaches: top-down approaches, which use mechanical devices Many previous researchers have demonstrated the ability of nanoparticles to encapsulate and deliver antivirals (Table 3) Nanoliposomes can be produced using a variety of different fabrication methods (Khorasani, Danaei et al. 2018 ). In the laboratory, they are often prepared using a solvent evaporation approach that involves several steps: dissolve phospholipids in organic solvent; place organic solvent in a glass

Journal Pre-proof flask; remove organic solvent by drying (resulting in phospholipid bilayers forming on the flask surface); and, finally add water (causing the phospholipid bilayers to peel off the flask and form nanoliposomes). This approach is not suitable for large scale production of nanoliposomes, but other methods can be used. For instance, mechanical dispersion methods such as sonication, homogenization, or microfluidization (Akbarzadeh, Rezaei-Sadabady et al. 2013) . Antivirals can be encapsulated by adding them to the phospholipids before nanoliposome formation or by incorporating them into the liposomes after their formation. Nanoliposomes can be used to deliver both lipophilic and hydrophilic antivirals because they contain both non-polar (phospholipid tails) and polar (phospholipid heads) domains within the bilayer structures (Demirci, Caglar et al. 2017) . Because nanoliposomes are formed from phospholipids they tend to be non-toxic, biocompatible, potentially minimally immunogenic, and biodegradable, which means they are particularly suitable for oral administration, as well as by other routes. However, nanoliposomes have been formulated in ways to elicit an immune response in multiple applications (Zamani, Momtazi-Borojeni et al. 2018) , suggesting that potential immune reaction should be a consideration before their application. In addition, the surfaces of nanoliposomes can be functionalized by incorporating specific ligands, thereby enhancing their ability to deliver antivirals to specific targets. However, there are also some potential limitations to their widespread application such as relatively high costs and low physicochemical stability (Akbarzadeh,

The ability of cationic nanoliposomes to improve the antiviral activity of suramin against noroviruses has been investigated (Mastrangelo, Mazzitelli et al. 2014 ). The activity of this antiviral agent is normally limited by its low permeability through cell membranes and poor cell internalization.

The authors used a mouse model to show that these hurdles could be overcome by using the nanoliposome delivery systems. In another study, PEGylated nanoliposomes (d = 181 nm) were developed for targeted delivery of interferon alpha-2b (IFN α-2b) to inhibit human papilloma virus J o u r n a l P r e -p r o o f (HPV) (Jøraholmen, Basnet et al. 2017) . A study showed that IFN α-2b loaded nanoliposomes had better penetration through the sheep vaginal tissue than the free form of IFN α-2b. When the surfaces of the nanoliposomes was functionalized with PEG, they could more easily penetrate deeper into the epithelium. This phenomenon was attributed to the presence of the neutral PEG molecules, which inhibit the adhesive interactions of the nanoliposomes with mucus, thereby allowing them to pass through more easily. In another study, antibody-coated nanoliposomes (d = 100-230 nm) were developed to increase the efficacy of an antiviral agent (dapivirine) against HIV (Wang, Michiels et al. 2016 ). These nanoliposomes could inhibit HIV through two complementary mechanisms: (i) the virus neutralizing effects of the antibodies (Vhhs); (ii) the antiviral activity of the dapivirine.

Nanoemulsions are another kind of colloidal system that has great potential for the encapsulation, an antiviral drug (acyclovir) that is effective against herpes, which was attributed to their ability to increase its permeation into the skin (Schwarz, Klang et al. 2012) .

Nanoemulsions have also been developed for the delivery of antiviral agents through the nasal route. The HIV-1 virus is known to be present within the human central nervous system but is difficult to treat because of the low permeability of anti-HIV drugs through the blood-brain barrier (BBB). To overcome this problem, researchers have encapsulated a hydrophobic antiviral agent (saquinavir mesylate), a protease inhibitor, in O/W nanoemulsions fabricated using the spontaneous emulsification method (Mahajan, Mahajan et al. 2014 ). The optimized nanoemulsion formulation was shown to increase the permeation of the antiviral agent into sheep nasal mucosa, and to increase the amount reaching the brain after intranasal administration to sheep. This study highlights the potential of nanoemulsion-based delivery systems administered nasally for treating viral infections in the central nervous system.

Nanoemulsion-based delivery systems can also be used to deliver antiviral agents via the intravenous route. O/W nanoemulsions have been shown to be effective at increasing the amount of a hydrophobic antiviral agent (Indinavir), another protease inhibitor, reaching the brain when administered intravenously (Prabhakar, Afzal et al. 2013 ). This effect was attributed to the ability of the nanoemulsions to increase the amount of the antiviral agent that was incorporated into the lipoproteins that carry hydrophobic substances around the bloodstream, as well as because the formulation contained known efflux inhibitors (Tween 80). Nanoemulsions have also been shown to be effective at delivering monoclonal antibodies via intravenous injection in a humanized mouse study (Pardi, Secreto et al. 2017 ).

Finally, nanoemulsions may also be suitable for the oral delivery of antiviral agents.

Encapsulation of efavirenz, a hydrophobic antiviral agent that operates by inhibiting a reverse transcriptase enzyme, within O/W nanoemulsions increased its antiviral activity against HIV (Senapati, J o u r n a l P r e -p r o o f Journal Pre-proof Sahoo et al. 2016) . The efavirenz was incorporated into a formulation that included a mixture of surfactants, oils, permeation enhancers, and efflux inhibitors so as to increase its oral bioavailability.

After ingestion, an O/W nanoemulsion containing small efavirenz-loaded lipid droplets was spontaneously formed. These droplets would be rapidly digested in the small intestine, thereby releasing the antiviral agent into mixed micelles that could transport it to the epithelium cells where it is absorbed.

In many respects, the structure of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) is similar to that of O/W nanoemulsions, except that the lipid phase inside the nanoparticles is solid rather than liquid (Müller, Mäder et al. 2000 , Weiss, Decker et al. 2008 ). In the case of SLNs, the lipid phase is completely solidified into a highly regular crystalline structure, whereas for NLCs the lipid phase is only partially solidified and has a more irregular crystalline structure. SLNs are therefore typically formed from pure lipids with a well-defined melting point, whereas NLCs are often formed from mixtures of lipids that have a broad melting range. Hydrophobic bioactive components are accommodated within the solidified lipid matrix of SLNs and NLCs. The presence of a solidified lipid phase can slow down molecular diffusion processes, which may inhibit the degradation or release of the bioactive components if designed correctly. However, the highly regular crystalline lipid phase in SLNs can lead to bioactive expulsion or particle aggregation (due to particle morphological changes) (Weiss, Decker et al. 2008 ). These problems can be overcome using NLCs since the irregular crystalline structure can accommodate more of the bioactive compounds (Müller, Radtke et al. 2002 , Weiss, Decker et al. 2008 .

SLNs and NLCs have been used for the encapsulation and delivery of various types of antiviral agent. For instance, SLNs (d = 167 nm) have been used to deliver atazanavir, an antiviral that works as a protease inhibitor, to the brain using a cell culture model of the blood-brain barrier (Chattopadhyay, J o u r n a l P r e -p r o o f Zastre et al. 2008) . Encapsulation of the antiviral increased the amount accumulating in the endothelial cells, which may lead to improvements in its ability to tackle HIV-encephalitis. Both SLNs and NLCs have been investigated for their ability to increase the ocular bioavailability of the antiviral agent acyclovir (Seyfoddin and Al-Kassas 2013) . The NLCs were shown to have a higher encapsulation efficiency and efficacy than the SLNs, which was attributed to the less regular lipid crystalline structure. SLNs have also been developed as topical delivery systems for an antiviral essential oil (Artemisia arborescens) . The authors showed that the essential oil could be successfully encapsulated within the SLNs. In an ex-vivo experiment with pig skin, the authors showed that the nanoemulsions increased the accumulation of the antiviral agent on the surface of the skin, but reduced its penetration into the skin (when compared to a pure oil formulation). They also showed that encapsulation of the antiviral agent did not adversely impact it's in vitro activity against Herpes Simplex Virus-1 (HSV-1). Taken together, the authors proposed that the SLNs would be a good formulation for antiviral agents intended for dermal applications. Ritonavir has been encapsulated in SLNs and shown to exhibit sustained release properties and antiviral activity using an in vitro anti-HIV-1 model ).

El-Gizawy, El-Maghraby et al. (2019) designed a SLN-based system for brain targeting of acyclovir. The SLNs were formulated from a variety of lipids and surfactants, and the nanoparticles were coated with chitosan to make them cationic. The authors showed that the acyclovir-loaded SLNs could deliver the antiviral agent to the brain through the BBB and that they remained in circulation for a longer time than the free form of the drug. This increased efficacy was partly attributed to the ability of the surfactants in the formulation (Pluronic ® F68 and Tween 80) to block the action of the Pglycoprotein efflux system, as well as to facilitate their transport across the BBB. The cationic chitosan molecules at the surfaces of the SLNs may have enhanced their transport through the BBB by interaction interacting with anionic domains on the membranes of the brain endothelial cells.

A wide variety of biopolymer-based nanocarriers can be produced from proteins, polysaccharides, and their complexes (Matalanis, Jones et al. 2011 ). Many of these nanocarriers can be used as antiviral delivery systems. Typically, these colloidal dispersions consist of small particles that contain a network of crosslinked biopolymer molecules. When the particles are predominantly composed of biopolymers they are referred to as nanoparticles, but when they are predominantly composed of solvent they are referred to as nanogels. Biopolymer particles can be fabricated through a variety of bottom-up and top-down methods, including injection-gelation, antisolvent precipitation, emulsiontemplating, thermodynamic incompatibility, molding, fragmentation, and coacervation approaches (McClements 2017 , McClements 2018 . The composition, dimensions, morphology, and surface characteristics of the biopolymer particles can be modulated by selecting appropriate ingredients and fabrication methods, which enables them to be tailored for specific applications.

Chitosan nanoparticles are one of the most popular biopolymer-based nanoparticles that have been used for targeting delivery of antivirals, because these provide high drug encapsulation efficiency, prolonged-release, and low cytotoxicity. Donalisio, Leone et al. (2018) loaded acyclovir in chitosanbased nanoparticles for treatment of HSV-1 and HSV-2. These nanoparticles successfully improved the topical delivery of acyclovir through the skin by increasing its permeability compared to its free form.

In vitro studies showed higher antiviral activity of acyclovir-loaded nanoparticles against both HSV strains. Russo, Gaglianone et al. (2014) showed that chitosan nanoparticles could deliver an antiviral agent (foscarnet) to lung fibroblasts (HELF) cells infected by the human cytomegalovirus (HCMV).

The authors showed that the antiviral activity of foscarnet was enhanced by encapsulation in the chitosan nanoparticles, which was related to the ability of the chitosan to prolong the circulation and enhance the mucoadhesion of the nanoparticles.

The ability of PLGA-TPGS nanoparticles to overcome the barriers associated with the ocular delivery of the antiviral agent acyclovir have been investigated (Alkholief, Albasit et al. 2019) . Here, PLGA (poly(lactic-co-glycolic acid)) is a biodegradable polymer and TPGS (D-α-Tocopherol polyethylene glycol 1000 succinate) is a synthetic surface-active material that releases vitamin E to cell

membranes. An ocular irritation study using rabbits showed that the acyclovir-loaded nanoparticles were non-irritant and non-toxic to the eyes. The authors also reported that encapsulation of the antiviral agent increased its ocular bioavailability compared to the free form. In another study, Ayoub, Jasti et al. (2020) showed that the antiviral agent entecavir could be encapsulated in PLGA nanoparticles and its release could be controlled by manipulating the formulation. The authors also used an in vivo study to show that the bioavailability of the entecavir was increased after encapsulation, which could lead to an effective approach for treating the hepatitis B virus.

Protein-based nanoparticles can also be used to effectively encapsulate and deliver antivirals. Suwannoi, Chomnawang et al. (2017) produced acyclovir-loaded bovine serum albumin (BSA) nanoparticles to treat ocular herpes viral infections. This study reported that encapsulation increased the transport of the acyclovir through the multilayers of the corneal epithelial cells, which was related to the small size of the nanoparticles. In another study, Fodor-Kardos, Kiss et al. (2020) showed that interferon-beta-1a (IFN-β-1a) could be successfully incorporated into biopolymer-based nanoparticles fabricated from BSA and pegylated PLGA polymers. Cyclodextrins (CDs) are a family of cyclic oligosaccharides that have been also been used to encapsulate antivirals within their hydrophobic cores (Pinho, Grootveld et al. 2014) .

Hybrid nanoparticles can be used to create antiviral delivery systems that combine the beneficial attributes of different individual nanoparticles. For example, hybrid nanoparticles can be formulated by trapping smaller particles inside larger particles, or by forming core-shell structures, which can lead to J o u r n a l P r e -p r o o f improved encapsulation, protection, or release properties (Zhang, Chan et al. 2008 , Chan, Zhang et al. 2009 ).

Alginate and stearic acid-polyethylene glycol (SA-PEG) were used in the formulation of a nanoparticle delivery system for zidovudine ). In this system, the zidovudine and alginate were used as core materials, while the SA-PEG was used as a shell. This combination led to the formation of a dendritic structure with internal voids and channels. An in vitro study showed that the hybrid nanoparticles were nontoxic, had good blood compatibility, and could deliver the antiviral agent to model brain cells. This type of hybrid nanoparticle may therefore be suitable for tackling HIV infections. In another study, core-shell hybrid nanoparticles were developed to encapsulate and deliver zidovudine. These nanoparticles consisted of a zidovudine-carboxymethylcellulose (CMC) core Liposomes containing essential oils were stable at least for six months. Antiviral assays demonstrated that the liposomal incorporation of A. arborescens essential oil enhanced its in vitro antiherpetic activity especially when vesicles were made with P90H. (Sinico, De Logu et al. 2005) Gel nanoemulsion Low energy method. Acyclovir Acyclovir permeation of optimum gel nanoemulsion was about 2.8-fold higher than the uncoated Acyclovir. This can be used as an appropriate delivery system to use topically for the treatment of viral ophthalmic disease. (Mahboobian, Mohammadi et al. 2020) Microemulsion

Obtained from pseudoternary diagrams.

Acyclovir A cationic charge-inducing agent, L-alanine benzyl ester, was added to the formulations to prepare positively-charged microemulsions. The presence of oleyl alcohol or oleic acid increased the flux but not the drug skin accumulation compared to a control suspension, while the use of the cationic charge-inducing agent had no influence on the formulation performance. Significantly optimizing drug targeting, maintaining the structure of the stratum corneum intact. (Peira, Chirio et al. 2009 )

Obtained from pseudoternary diagrams.

Microscopic examination after in vivo skin irritation studies using mice suggested few histological changes in the skin of animals treated with the ME compared to the control group (hydrogel). Higher permeability of zidovudine through skin. (Carvalho, da Silva et al. 2016) Nanoliposome Lipid film hydration method.

Promoted the prolonged contact between the drug and the absorptive sites in the nasal cavity, and facilitated direct absorption through the nasal mucosa. (Alsarra, Hamed et al. 2008) Hybrid nanoparticles Dextran and stearic acid nanoparticles Double emulsion solvent evaporation method.

Higher cellular internalization of drug loaded hybrid nanoparticles. The results showed the feasibility and efficacy of the hybrid nanoparticles for effective delivery of zidovudine (Joshy, George et al. 2018) J o u r n a l P r e -p r o o f Thiolated chitosan (TCS) core/shell nanofibers A coaxial electrospinning technique.

The core/shell NFs were 40-60-fold more bioadhesive than the pure PEO based nanofibers. The nanofibers were nontoxic and noninflammatory in vivo after daily treatment for up to 7 days. The TCS core/shell NFs are promising candidates for the topical delivery of HIV/AIDS microbicides such as tenofovir. (Meng, Agrahari et al. 2016) Lipid-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles A modified singleemulsion evaporation method.

Latency-reversing agentscombination that displayed synergistic latency reversal and low cytotoxicity in a cell model of HIV and in CD4 + T cells from virologically suppressed patients. Selectively activated CD4+ T cells in nonhuman primate peripheral blood mononuclear cells as well as in murine lymph nodes, and substantially reduced local toxicity. 

Significant improvement in cellular internalization. It is envisaged that nanoparticles composed of lipid and polymer moieties may constitute a preferred embodiment for anti-viral drug delivery for use in HIV/AIDS therapy. Nanoparticles are composed of carboxy methyl cellulosezidovudine core enclosed by a compritol (Comp)-polyethylene glycol shell.

Higher encapsulation efficiency, nontoxic, targeted releases, effectively penetrate to the brain cells were acieved by hybrid nanoaprticles. (Joshy, Snigdha et al. 2017) J o u r n a l P r e -p r o o f Journal Pre-proof

Nano-enabled delivery systems can be designed to enhance the efficacy of many antiviral agents by overcoming physicochemical and biological barriers, such as low solubility, poor stability, matrix interactions, low bioavailability, untargeted release, undesirable side effects, and development of antiviral resistance. Many kinds of delivery systems are available for this purpose, such as micelles, microemulsions, nanoliposomes, nanoemulsions, solid lipid nanoparticles, biopolymer nanoparticles, and biopolymer nanogels. Each of these delivery systems has its set of advantages and disadvantages for certain applications. It is therefore important to select the most appropriate one and then optimize its formulation. At present, many researchers do not try to rationally identify the most appropriate delivery systemthey simply select one type of delivery system they are familiar with and then investigate its potential. There is currently a lack of systematic studies that compare different kinds of delivery systems for a particular application to identify the most suitable one. This area would certainly benefit from the creation of standardized methods to systematically test antiviral agents against specific viruses using different kinds of delivery systems. These methods could then be used to compare the relative merits of different systems. Fig. 1 . Different antiviral delivery routes.

Non-invasive route for antivirals.

Require pass through The most effective route for emergencies.

Discomfort, cost, and

Advantages:

Low side effects and toxicity.

Expensive.

J o u r n a l P r e -p r o o f 

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