key: cord-1002418-xwhljffn authors: Wang, Li; Wang, Zhaoshuo; Cao, Lingzhi; Ge, Kun title: Constructive strategies for drug delivery systems in antivirus disease therapy by safety materials date: 2022-03-11 journal: Biosaf Health DOI: 10.1016/j.bsheal.2022.03.008 sha: c78e55d224a7c8041560ffebcbec0d33e52ec54e doc_id: 1002418 cord_uid: xwhljffn Due to the COVID-19 pandemic, the development of antiviral drugs has attracted increasing attention. Clinical antiviral drugs show weak solubility, low bioavailability, adverse side effects, or only limited targets. With the advancement of nanotechnology and material science, biosafety nanomaterials have been constructed for drug delivery systems of antiviral disease therapy, such as liposomes, polymers, gold nanoparticles, and graphene. These nanodrug systems can either deliver synthesized antiviral drugs siRNA/miRNA and small molecular compounds, deliver bioactive large molecular drug proteins and mRNA, or show antiviral activity by themselves. Nanodelivery systems could effectively enhance the efficiency of antiviral drugs by increasing drug loading and host cell uptake with a small size and high specific surface area. This review focused on the biosafety nanomaterials used for antiviral therapy and discussed the options for the design of antiviral drugs in the future. Viral infection is a serious threat to global public health. It is estimated that viruses cause approximately two million deaths each year [1] . and their variants, as best exemplified by the COVID-19 global pandemic. Therefore, the development of antiviral drugs is an effective way to combat viral infections [1] . Currently, drugs such as enfuvirtide, maraviroc, indinavir, acyclovir, peptides and nucleic acids have been used in the treatment of viral infection in the clinic. Moreover, a number of natural small molecule drugs have been applied in clinical studies, such as curcumin, a natural phenolic compound that has been shown to have antiviral activity [2] . Biologically active antiviral drugs are also being investigated. The antiviral mechanisms of small molecule drugs and biologically active molecules are different. The antiviral mechanism of small molecule drugs is mostly to inhibit virus infection in the body by interfering with virus adsorption and penetration, while biologically active molecules inhibit virus infection by interfering with virus DNA translation and transcription in the body. Although all of these drugs have shown excellent antiviral activity in in vitro studies, there are still many issues that limit their efficacy in the clinic, such as poor solubility, poor stability during storage or application, low bioavailability, the emergence of medication resistance, potential adverse side effects or toxicity [3] . With the development of nanomaterials, these drug delivery systems have shown great potential for antiviral drug encapsulation, stability and activity [4] . Accordingly, the application of nanobiosafety materials is becoming increasingly widespread. Recently, nanoparticles such as liposomes (LNP) and polymers have attracted attention due to their wide range of functions, low biotoxicity, high biocompatibility and good biodegradability. Due to differences in the composition, structure and functional properties of nanodelivery systems, researchers have designed nanocarrier systems suitable for different antiviral drugs. The small particle size and high specific surface area of antiviral nanodelivery carriers facilitate increased drug loading and entry into host cells, improving the efficacy of antiviral drugs (Table 1) . Moreover, there are metal-based and carbon-based nanomaterials that have inherent antiviral properties. Some of them have shown antiviral efficiency by stopping viruses from entering host cells for replication or inhibiting virus replication [5] . Therefore, this review summarizes the use of nanomedicines in antiviral therapy using different materialbased drug delivery systems developed in recent years and it discusses the prospects and challenges of antiviral nanostructures in the future. [6] and first recognized phospholipids as closed bilayers in aqueous systems [7] . The use of LNP was also documented as early as 1973, when the use of LNP encapsulated with ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid to alleviate plutonium poisoning increased urinary excretion of plutonium and prolonged survival in mice [8] . VZV is a neurophilic and lymphophilic alpha herpesvirus that causes varicella and Among the antiviral drug delivery systems, polymers have been widely used due to their unique structural characteristics (Table 1) Polymers can protect small molecule compound drugs from degradation and immune escape. Chloroquine diphosphate (CQ) has attracted much attention due to its anti-HSV-1 virus activity, but it is difficult to achieve an effective therapeutic concentration in the cell. CQ-loaded D,L-poly(lactic acid) nanoparticles were prepared by an improved emulsification-solvent evaporation method ( Fig. 2D and E) , which effectively improved the antiviral activity of the drug [15] . To achieve the sensitivity and high entrapment efficiency of drug inside the cells, Shaymaa Shawky et al. which showed that the release rate of SOF could be effectively reduced [16] . IAV is seasonal and highly infectious, and although research and development of related drugs has been ongoing, the rapid mutation of the virus and the development of drug resistance have kept the problem of influenza unresolved. Against this background, Chun et al. [17] proposed amphiphilic polymeric delivery vehicles (PBASomes) modified by conjugation with phenylboronic acid (PBA, which interacts with sialic acid residues on the cell surface through the formation of hydrogen bonds between diol groups [18, 19] and which plays an important role in the attachment of IAV and the binding of PBA [20] ) could be used to deliver miR323a (an intracellular drug that interferes with RNA virus polymerase and binds to the PB1 gene of the H1N1 virus [21] ) and favipiravir (a pseudopurine nucleotide) into the host cell simultaneously, and through this combined administration thereby improving antiviral efficacy. The polymer was self-assembled from a mixture of a methoxy-poly (ethylene glycol)-blockpoly(phenylalanine) (mPEG-b-Phe) amphiphilic copolymer and a PBA conjugated polymer (PBA-PEG-b-pPhe). MiR323a and favipiravir were encapsulated in the core and bilayer of PBASomes, respectively. Their results showed that miR323a and favipiravir significantly enhanced the therapeutic effect of miR323a and favipiravir against H1N1 virus infection. In addition, RME induction and cell structure simulation demonstrated that PBASomes have the advantages of good intracellular uptake, slow release and low cytotoxicity and can be used as efficient combination drug carriers for IAV treatment. A neutralizing monoclonal antibody can specifically neutralize a virus and prevent it from entering the cell to proliferate. It can be used as short-term prevention among high-risk populations and for the treatment of diseases after viral infections such as HIV. During combined antiretroviral therapy of HIV, it has been found that intestinal-related lymphoid tissues can quickly establish HIV virus reservoirs within HIV-infected patients, which can lead to drug resistance that is hard to treat [22] . Cao designed a core-shell nanosystem comprised of a PLGA core and a phospholipid bilayer shell [23] . For coupling α4β7 monoclonal antibodies (α4β7-LCNPs), researchers coated PEG on the surface of the shell. To prevent infected cells from producing new HIV particles in GALT, protease inhibitors were also encapsulated in LCNPs. Additionally, the nanosystem was loaded with tipranavir (TPV). The results showed that the LCNP system can deliver antiretroviral drugs and monoclonal antibodies to HIV host cells to reduce their viral load. In addition to the two main classes of nanocarriers, LNP and polymers, researchers have proposed a number of other structured nanocarriers for the delivery of viral infections. Moreover, some nanomaterials showed antiviral effects themselves ( Table 2 ). For instance, silver nanoparticles (AgNPs) are able to bind to viral surface proteins, thus preventing the virus from entering the cell by contacting receptor proteins on the surface of the cell membrane [24] . For the purpose of this review, we classified these carriers into metal nanocarriers, carbon-based nanocarriers, protein carriers and hybrid nanocarriers. Nucleic acids Protecting partial modification of oligonucleotides and inter-nucleotide bonds [32] Carbon dots --Modulating IFN to inhibit viral replication at an early stage of infection [38] Albumin AgNPs have shown promising efficacy in the antibacterial and antiviral fields [25] . AgNPs can bind viral surface proteins and inhibit the interaction between viruses and cell membrane receptors (Fig. 3A) . It has also been reported that AgNPs can inactivate viruses by denaturing surface proteins containing cysteine and methionine residues on the viral capsid. For instance, AgNPs smaller than 10 nm have been shown to interact with the sulfur-containing residues of the gp120 glycoprotein, which is distributed on the lipid membrane of HIV-1 virus and can prevent the virus from binding to the CD4 receptor site on the host cell, thereby suppressing viral infection [26] . However, it is essential to note that the antiviral properties of AgNPs are determined by their specific particle structure in solution and not by the silver ions themselves [27] . Particularly for pandemic viruses with surface proteins capable of rapid mutation, new treatment strategies for targeted hemagglutinin are more applicable than conventional therapies [29] . Moreover, the antiviral activity of AuNPs correlates with the surface area exposed, with the larger the surface area, the higher the antiviral activity. Thus, the size and modality of these AuNPs play an important role in their antiviral activity. Chattopadhyay et al. [30] prepared highly monodisperse spherical gold nanoparticles for the inhibition of HSV. The experimental results showed that the monodisperse gold nanoparticles effectively prevented HSV from attaching and entering Vero cells, and their cytotoxicity was lower than that of acyclovir ( Fig. 3 B and C). Kim et al. [31] found that porous AuNPs were more effective in inhibiting influenza A virus infection than nonporous AuNPs. This was related to the higher surface area of the porous material, with the higher surface area facilitating the interaction of AuNPs with the envelope, thereby increasing their antiviral activity. Titanium-based nanoparticles have become a popular material for nanodelivery due to their low toxicity, good stability and cell membrane permeability. In recent years, nucleic acid delivery has become a major area of research in antiviral therapy. How to achieve efficient delivery of nucleic acids has become an issue of great interest to researchers in various countries. The ability of titanium dioxide nanoparticles to protect the modified portion of oligonucleotides has attracted attention. Levina et al. [32] developed TiO2PL-ODN, a crystalline form of titanium dioxide nanoparticles containing oligonucleotides. They first synthesized phosphodiester-modified oligonucleotides, which were then combined with titanium dioxide to obtain TiO2PL-ODN nanoparticles. The experimental results showed that the mouse-targeted oligonucleotides in the nanocomposites had the ability to interact with complementary RNAs, which verified that titanium dioxide nanoparticles provide protection against partial modification of oligonucleotides and internucleotide bonds in nanocomposites. The In addition to adhesion to host cells through recognition of GPs, viruses can also bind heparan sulfate (HS) on the surface of host cells [34] to achieve attachment of viral particles and entry into susceptible cells (HS is a negatively charged linear polymer consisting of alternating hexoses and glucosamine, which are sulfated at different locations). [35] ). Whereas graphene has excellent thermal conductivity, it has been demonstrated that graphene can be used in photothermal therapy and photodynamic therapy for bacterial inactivation [36] . Therefore, the functionalized modification of graphene with HS not only enables the capture of viruses but also their inactivation by photothermal conversion. Archana R. Deokar et al. [37] designed a sulfonated magnetic nanoparticle prepared using functionalized reduced graphene oxide (SMRGO) to achieve the capture and photothermal inactivation of HSV-1 viruses (Fig. 4 A-C) . Albumin is the most abundant plasma protein and it plays a crucial role in regulating the colloid osmotic pressure of plasma and transporting various lipid-soluble endogenous compounds. Over the past decades, albumin has been widely used as a nanodrug carrier due to its better biocompatibility, low immunogenicity and wide Exosomes are nanoscale (40-100 nm) vesicles secreted by cells that play an important role in intercellular material transport and signaling [42] . Exosomes are similar in size and function to synthetic nanostructures, but as natural endogenous transport carriers, they have the advantages of low toxicity, nonimmunogenicity and good penetration and therefore may become more viable drug delivery vehicles [43] . In addition, exosomes can be extracted from patient fluids or cells and they have a higher biosafety profile than other nanodelivery vehicles [44] . Additionally, exosomes carrying cell surface molecules have a high adsorption capacity, are able to overcome various biological barriers and are naturally targeted, making exosome delivery systems well suited as delivery vehicles for antiviral therapy [45] [46] [47] . To achieve long-term suppression of HIV-1 virus and to reduce the side effects of treatment, Surya Shrivastava et al. [48] designed an HIV-1 promoter targeting zinc finger protein (ZFP-362), which was integrated into the active region of DNA methyltransferase 3a and could continuously suppress epigenetic inheritance of HIV-1. Although, in the above discussion of carriers, we have detailed their respective structural characteristics and therapeutic advantages, single structural types of carriers tend to have their own drawbacks. Therefore, researchers have developed the concept of hybrid nanocarriers to maximize the therapeutic effects. The Advances in biomaterials promote the development of nanomedicine. In the above discussion, it is easy to see that each type of nanodrug delivery system has its own advantages. LNP, which are mainly formed from phospholipids, are nontoxic, biocompatible and biodegradable and can also reduce the toxic effects of carrier molecules, which means they are particularly suitable for oral or other routes of drug delivery. Polymers have various compositions, sizes, morphologies and surface properties that can be adjusted by applying different ingredients and manufacturing methods for specific applications. Tailoring polymers can improve organ selectivity by introducing targeting groups. Meanwhile, some inorganic nanoparticles, such as AgNPs and AuNPs, can bind to viral surface receptors and prevent viruses from entering the host cell. However, it is important to note that LNP has been shown to induce immune reactions on several previous occasions, suggesting that potential immune reactions should be considered. In addition, although inorganic nanoparticles or nanodelivery systems have good antiviral activity, they are difficult to degrade in living organisms and tend to accumulate in the body, causing organ toxicity. In contrast, cationic polymers can bind to negatively charged cell membranes to increase permeability and facilitate endocytosis, but they also show cytotoxicity by damaging the cell membranes and reducing the DNA release rate. Therefore, some factors need to be considered when developing nanodrugs for antiviral therapy. First, the choice of nanodelivery systems depends on the characteristics of the antiviral drug. For example, the activity of the antiviral drug suramin is often limited by its difficulty in penetrating cell membranes and poor cellular internalization, and the use of cationic LNP can overcome this obstacle very well. To inhibit the adhesion of LNP to mucus and make it easier to pass through epithelial cells, LNP can be modified with PEG to improve their molecularly neutral nature. Second, as a drug delivery vehicle, the efficiency of drug release at the targeted site is also a key problem that needs to be considered. Nucleic acid drugs, for example, are of great interest because of their ability to act directly on disease-causing target genes or target mRNAs to treat disease at the genetic level. However, nucleic acid drugs are susceptible to degradation by RNase enzymes in vivo, and it is difficult to achieve lysosomal escape, resulting in a failure to achieve effective drug concentrations at specific target sites. Multitailed ionizable phospholipids can facilitate membrane transformation in acidic endosomal environments and subsequently release nucleic acid drugs from endosomes [52] . Finally, the development of universal vectors for different virus species also needs to be considered. With so many different types of viruses and variants, a single antiviral system is no longer the answer to today's pandemic dilemma, and the development of universal antiviral nanodelivery systems to achieve broad-spectrum antiviral therapy is a major trend for the future. 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Influenza Other Respir Viruses Cellular microRNAs inhibit replication of the H1N1 influenza A virus in infected cells Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy Core-shell nanoparticles for targeted and combination antiretroviral activity in gut-homing T cells Metal nanoparticles: The protective nanoshield against virus infection Silver nanoparticles as a new generation of antimicrobials Interaction of silver nanoparticles with HIV-1 Silver nanoparticles impair Peste des petits ruminants virus replication The inhibition of H1N1 influenza virus-induced apoptosis by silver nanoparticles functionalized with zanamivir Changes in vitro susceptibility of influenza A H3N2 viruses to a neuraminidase inhibitor drug during evolution in the human host Highly monodispersed gold nanoparticles synthesis and inhibition of herpes simplex virus infections Porous gold nanoparticles for attenuating infectivity of influenza A virus Pronounced therapeutic potential of oligonucleotides fixed on inorganic nanoparticles against highly pathogenic H5N1 influenza A virus in vivo Synthesis of giant globular multivalent glycofullerenes as potent inhibitors in a model of Ebola virus infection Mutational analysis of the major heparan sulfate-binding domain of herpes simplex virus type 1 glycoprotein C Nanostructures for the inhibition of viral infections Graphene-based photothermal agent for rapid and effective killing of bacteria Graphene-based "Hot Plate" for the capture and destruction of the herpes simplex virus type 1 Carbon dots as inhibitors of virus by activation of type I interferon response. Carbon Multisite inhibitors for enteric coronavirus: antiviral cationic carbon dots based on curcumin PEGylated nanoparticle albumin-bound steroidal ginsenoside derivatives ameliorate SARS-CoV-2-mediated hyper-inflammatory responses Polymeric pathogen-like particles-based combination adjuvants elicit potent mucosal T cell immunity to influenza A virus Exfoliation of membrane ecto-enzymes in the form of microvesicles The role of extracellular vesicles in phenotypic cancer transformation Host matrix modulation by tumor exosomes promotes motility and invasiveness Extracellular vesicles expressing a single-chain variable fragment of an HIV-1 specific antibody selectively target Env (+) tissues. Theranostics Exosome-based nanocarriers as bio-inspired and versatile vehicles for drug delivery: recent advances and challenges RNA delivery by extracellular vesicles in mammalian cells and its applications Exosome-mediated stable epigenetic repression of HIV-1 Exosomes cause preterm birth in mice: evidence for paracrine signaling in pregnancy EVs containing host restriction factor IFITM3 inhibited ZIKV infection of fetuses in pregnant mice through trans-placenta delivery Heteromultivalent topology-matched nanostructures as potent and broad-spectrum influenza A virus inhibitors Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR-Cas gene editing Highlights Liposomes and polymers are particularly suitable for drug delivery in antivirus therapy due to their biocompatibility Some inorganic nanoparticles, such as AgNPs and AuNPs, can act directly on viruses The authors declare that there are no conflicts of interest.