Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to COVID-19 and has become a pandemic worldwide with mortality of millions. Nanotechnology can be used to deliver antiviral medicines or other types of viral reproduction-inhibiting medications. At various steps of viral infection, nanotechnology could suggest practical solutions for usage in the fight against viral infection. Nanotechnology-based approaches can help in the fight against SARS-CoV-2 infection. Nanoparticles can play an essential role in progressing SARS-CoV-2 treatment and vaccine production in efficacy and safety. Nanocarriers have increased the speed of vaccine development and the efficiency of vaccines. As a result, the increased investigation into nanoparticles as nano-delivery systems and nanotherapeutics in viral infection, and the development of new and effective methods are essential for inhibiting SARS-CoV-2 infection. In this article, we compare the attributes of several nanoparticles and evaluate their capability to create novel vaccines and treatment methods against different types of viral diseases, especially the SARS-CoV-2 disease.

Graphical Abstract

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Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), a worldwide pandemic of COVID-19 resulting in over 5.8 million deaths and over 414 million infected people recovering [1, 2]. Major COVID-19 infected patients have reportedly had mild to acute respiratory infections with symptoms such as fever, cough, and dyspnea, which might emerge 2–14 days afterward exposure to the infection [3, 4]. Public-health and non-pharmaceutical interventions have been important in reducing the speed of the prevalence of the COVID-19 infection. These interventions have been important in reducing the prevalence of the COVID-19, but given their considerable societal, economic and political expenses, substitute long-time solutions are required []. A vaccine remains the more encouraging one [5, 6]. Nanotechnology, with the advancement and usage of nanoparticles (NPs)/nanocarriers, has been broadly used in a diversity of fields [7–9]. The very small dimensions of NPs allow effective entry into living organizations. Additionally, nano biomedical knowledge has been the purpose of a considerable rate of consideration, such as efficient and targeted delivery of medicines, genes, and therapeutic molecules to particular organs or cells, imaging, and accurate diagnosis of viruses at initial steps [10, 11]. The NPs of silver, gold, silver sulfide, titanium oxide, zirconium, grapheme, and polymeric compositions can be utilized as a delivery system for vaccines, which have an extraordinary ability as compared to common antigen-based vaccines [12]. Furthermore, NPs have an essential function in antiviral treatment via increasing the transfer of hydrophobic medications and increasing medicine utilization effectiveness[13]. NP-based medicines can prevent viral diseases by inhibiting virus binding and entry into the cell, suppressing viral replication, and directly deactivating viruses. Different metal NPs, polylactic acid, etc., are broadly utilized for the therapy of COVID-19 [14].

In this paper, we discussed nanostructure, which is useful in the delivery and treatment of viral infection. In addition, this study focuses on several main features of SARS-CoV-2, including epidemiology, molecular structure, viral life cycle and immune characteristic of SARS-CoV-2, vaccine/treatment method, the role of NPs in improving prevention, and therapeutic strategies of COVID-19.

A brief overview of the important features of SARS-CoV-2 (epidemiology, molecular structure, and viral life cycle)

Coronaviruses (CoVs) are more divided phylogenetically into 4-sort, Alpha-, Beta-, Gamma-, and Delta-CoV, and also human CoVs can be mostly separated into types, α and β-CoV [15–17]. SARS-CoV-2 belongs to β-CoVs [18, 19] and leads to the COVID-19 pandemic, which contains asymptomatic upper and lower respiratory tract diseases [20, 21]. In addition, there is powerful proof that COVID-19 in brain can lead to multiple neurological disorders and changes ranging from nonspecific to moderate to acute situations [22]. CoVs are positive-sense, single-stranded RNA (+SS-RNA) [23]. The genome of this virus encodes several smaller open reading frames (ORFs). Structural proteins, including the spike (S) glycoprotein, envelope (E), membrane (M), nucleocapsid (N) proteins, and nonstructural proteins (NSP) are encoded by ORF [24]. The replicase gene of SARS-CoV-2 encodes two overlapping polyproteins that are necessary for viral reproduction and transcription [25]. In the 5′-UTR part, approximately more than two-thirds of the RNA comprises ORF1a/b [26, 27]. The RdRp actions in a holo-RdRp produce the whole viral genome [23]. In addition, CoVs are the main protease due to their necessary function in processing polyproteins [28]. Triggering of S needs cleavage of S1/S2 through furin-like protease and undergoes a structural alteration from prefusion to postfusion. As soon as triggered, S pursues a classic pathway between class I fusion proteins: it undergoes considerable conformational rearrangements. including shedding its S1 subunit and incorporating the fusion peptide (FP) in the host cell membrane [29]. The S2 subunit is membrane-anchored and harbors the fusion system [30]. SARS-CoV-2 S protein bind to the Angiotensin-converting enzyme 2 (ACE2) host cell [31]. As soon as prosperous entrance, the genomic RNA (sgRNA) SARS-CoV-2 acts as a transcript and lets the cap-affiliate translation of ORF1a generating polyprotein pp1a [32]. Then, the structural proteins are incorporated into membranes of the endoplasmic reticulum and transported to the endoplasmic reticulum–Golgi intermediate compartment (ERGIC). The encapsidated genome buds in the ERGIC create virions, which are afterward transported to the plasma membrane and discharged [33] (Fig. 1).

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Fig. 1

3D illustration of the structural and nonstructural protein of SARS-CoV-2 and target cell receptor (ACE2). In addition, this graphic demonstrates the entrance and replication (life cycle) of SARS-CoV-2 in target cells

To neutralize SARS-CoV-2 infection and future prevalence, robust, repeatable, affordable, high time-efficient vaccines, and novel medicine formulations, also preventive techniques, must be produced and approved. With these issues in mind, NPs methods have been widely reported and encouraged globally as an approach to fight and inhibit COVID-19. Therefore, the SARS-CoV-2 infection needs a serious evaluation of available nanotechnologies. Also, nanomedicine methods are being utilized to produce vaccine carriers and therapy of SARS-CoV-2 [34].

Nanoparticles-based strategies to fight against viral infections

NPs based on organic and inorganic compositions have been broadly investigated as novel vaccine methods because of their capability to induce the immune response and prepare sustained antigen discharge afterward vaccine injection. NPs can also prepare a regulated and low-speed discharge of antigens, generating a depot at the injection location supplying possible preservation versus antigen destruction [35, 36]. NP-based vaccine transfer methods designed to meet these standards have multiple benefits over conventional vaccines; (1) entrapment of antigens in NPs inhibits antigen destruction and enhance their constancy; (2) co-entrapment of antigen and immunostimulatory factor in NPs improves immunogenicity and capability of vaccines; (3) antigen-presenting cells (APCs) can easily phagocytose and procedure particles; and (4) surface decorations of NPs with functional moieties and targeting ligands allow organ- and cell-particular binding to lymphoid organs and APCs [37] (Fig. 2).

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Fig. 2

Summary of the pathways via which nanovaccines can create an immune reaction. a NPs can be utilized as a vaccine program for different infected illnesses because they can transport antigens and numerous immunostimulatory molecules (TLR ligands and adjuvants). The immunostimulatory action of nanovaccines is associated with different pathways, including the depot effect, gradual discharge of vaccine antigens, and absorption of antigen-offering cells. b Antigen transport via NPs (dimensions-related permeation and tissue or organ targeting). c Depot effect supplies a long-term and continuous discharge of constant antigen. d Cross presentation of the antigen transported via the NPs (cytosolic transport) triggers antigen particular cytotoxic T lymphocytes. Antigen-presenting cell (APC); endoplasmic reticulum (ER); T cell receptor (TCR) [38, 164]

Newly, nanomedicine was developed to entrap antiviral factors to (1) enhance pharmacokinetic parameters, and bioavailability, (2) increase medicine consistency, (3) regulate/sustain medicine discharge, (4) elective transport of medicine to a specific organ, and (5) pass the blood–brain barrier [38, 39]. The functional NPs can be utilized as a wide range of antiviral factors to inhibit the primary stage of viral disease, including viral binding to host cell receptors. The second method to inhibit viruses is obstructing their permeation and entrance to target cells via altering the external membrane of the cell and protein constructions. About virus entrance into the cell, destroying their reproduction is the third efficient method to prevent the virus, which is usually attained via inhibiting the expression of some enzymes that originally assist to complete the replication of the virus genome. The last approach prevents the virus budding and excreting it from host cells [40]. In addition, NPs are recently utilized as a new strategy to directly kill the viruses by directly damaging the structure of the virus [41].

Application of different nanoparticles against viral infections

NPs can be classified into two classes based on the ingredients of the structure: organic and inorganic [42, 43]. NPs as drug delivery systems, including antivirals, can suppress viral reproduction in host cells via discharged antivirals from NPs obstructing target cell receptors, and released antivirals from absorbed NPs in a target cell inhibit main viral replication stages containing transcription, replication of phage DNA and synthesis of protein, and assembly [44]. Potential mechanisms include neutralization of the virus per se or indirectly, inhibition of binding of viruses to target cells, and inhibiting viral reproduction; however, they relate to the shape and kind of NPs utilized [45] (Fig. 3).

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Fig. 3

Several NPs function in treating the viral infection as antiviral factors and delivery factors. a Several types of inorganic and organic NPs. b The mechanism of the NPs as a delivery system. c The mechanism of the NPs as an antiviral

SARS-CoV-2 immunopathology (innate and adaptive immune response)

Innate immunity commenced by detecting pathogen-associated molecular patterns (PAMPs) through host pattern recognition receptors (PRRs). The IFN-I pathway is an essential section of the innate immune reaction. PRRs diagnose many viruses, and this detection activates a downstream antiviral cascade such as microRNAs antiviral action [94, 98, 99]. The CoVs ds-RNA could be recognized via the retinoic acid-inducible gene I-like receptors (RLRs), comprising the RIG-I and, or melanoma differentiation gene 5 (MDA5) into the cytoplasm, or via TLRs within the endosome. The 2 caspase recruitment domains (CARD) of RIG-I and MDA5 could react to the adapter mitochondrial antiviral signaling protein (MAVS), which consequently induces the 2 IKK-associated kinases, TANK-binding kinase 1 (TBK1), and inducible IκB kinase (IKKi), together of which phosphorylate IFN regulatory factor 3/7 (IRF3/7). Afterward phosphorylation and dimerization, IRF3/7 replaces in the nucleus to trigger the expression of IFN-α/β. Simultaneously, MAVS induces TANK1 via TRAF6 and triggers the NF-κB signaling mechanism, which could increase cytokines generation. On the other hand, PAMPs could be recognized via TLRs, and the downstream adapter proteins TRIF or MyD88 could signal to activate cytokines and chemokines generation [100]. Signaling at these cell receptors stimulates cytosolic translocation of several nuclear transcription agents, including NF-kB and the activating protein-1 (AP-1) to the cell nucleus, the transcription of genes, and expression of critical inflammatory reaction proteins, including CRP, proinflammatory cytokines, and chemokines, also discharge of soluble agents related on the IFN protein stimulator gene (ISGs) that encodes IFNs function in virus regulator, activation anti-virus mode [101]. Afterward viral induction, IFNs are induced via the detection of PAMPs with PRRs, endosomal (TLR3 and TLR7), and cytosolic (RIG-I) receptors, such as triggering and phosphorylation of the JAK/STAT pathway and the creation of the heterotrimer compound STAT1-STAT2-IRF9 (ISGF3) that is involved in the stimulation of the genes accountable for the reactions to IFNs in the promoter section of the ISG. STAT1/2 generate a compound with IRF9, and together they transfer to the nucleus to begin the transcription of ISGs under the regulation of IFN-stimulated response element (ISRE) comprising promoters (Fig. 4) [101].

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Fig. 4

This illustration demonstrates the possible immunopathogenesis in COVID-19 infection (innate immunity, adaptive immunity, and humoral immunity)

In COVID-19 infected patients, the reports have shown that primary plasma measures of IL-1β, IL-1RA, IL-7, IL-8, IL-10, IFN-, monocyte chemoattractant peptide (MCP)-1, macrophage inflammatory protein (MIP)-1A, MIP-1B, granulocyte-colony-stimulating factor (G-CSF), and TNF-α are enhanced in COVID-19 patients. Moreover, the rate of helper T lymphocytes and cytotoxic T lymphocytes inhibitor (CD3+, CD8+), and regulatory T cells (Tregs) are lower than normal rates; however, T helper and Tregs in acute patients are significantly lesser than in mild cases [102, 103]. The SARS-CoV-2 binding to the target cell by the ACE-2 and is recognized (essentially) via TLR7. TLR7 activity results in the generation of IFN-α, and the release of IL-12 and IL-6. This leads to the creation of CD8+-particular cytotoxic T lymphocytes and, via the CD4+lymphocytes, results in the generation of antigen-particular B lymphocytes and antibody generation (IgM, IgG, and IgA (pan-immunoglobulin (pan-Ig)). In TLR7 signaling-associated cytokine discharge, IL-6 can play a significant function. It is essential in the formation of follicular CD4+lymphocytes, TH17 subgroup deflection, and the creation of prolonged lived plasma cells [104].

Therapeutic and prevention procedures of the SARS-CoV-2 infection

Mutations in the SARS-CoV-2 genome make it challenging to produce treatment methods. On the other hand, the high prevalence of this virus has led to the rapid development of an effective treatment method [105]. Therefore, different medical, social, and engineering techniques have been proposed to face the SARS-CoV-2 prevalence that contains treatment, prevention, diagnosis, and prediction methods. In addition, essential therapies were presented, including antiviral medicines (e.g., dexamethasone [106], Favipiravir [107], and Remdesivir [108]), antibiotics, oxygen therapy, and antibody therapy [109, 110]. In addition, utilized convalescent plasma technique for the therapy of COVID-19, which is an immunotherapy method by viral-particular antibodies [111]. Mainly, SARS-CoV-2 infection leads to remarkable injury to the lungs; therefore, pulmonary medication transfer must be included as a curative method for important action. In this context, aerosol-based intranasal injection route designs might be an improved method which is not only patient compliant but can as well show the quick relief over a specified period. In its pure form, bilirubin has difficulties with its solubility; therefore, its injection in NP form provides improved solubility and enhanced effectiveness. Bilirubin nanomedicine (BNM) as aerosol-based medication delivery method can carry payload directly to the lungs and decrease the complications of SARS-CoV-2 leading to enhanced patient condition [112].

Based on reports of the World Health Organization (WHO), on Jan. 31, 2022, vaccine candidates were in clinical assessment to remedy COVID-19, 114 vaccines in clinical assessment, and 48 candidate vaccines have attained the final phases of the trial [5, 113]. These vaccines include inactivated vaccines, nucleic acid vaccines, vector vaccines, and subunit vaccines. Inactivated vaccines are broadly utilized to inhibit emerging infectious diseases (EID), and the partly great speed of the generation of this type of vaccine makes it a hopeful method for COVID-19 vaccine production [114, 115]. These vaccines are complete virus formations that are chemically inactivated with beta-propiolactone and formaldehyde. However, they are no longer replication-ability, virus integrity is protected, and acts as an immunogen that is S-particular, RBD-particular and N-particular. When injected, inactivated vaccines induce preservative immune reactions against the pathogen. This type of vaccine is obtained from viruses grown in culture and next chemically inactivated, which can deliver stably expressed, structurally native antigenic epitopes (such as Sinopharm and Sinovac vaccines) [116]. Nucleic acid (RNA and DNA) vaccines are facile to produce, which allows their fast progress as vaccines. The genome encoding for a specific protein can be simply formed as DNA or RNA and introduced in human cells to generate several copies of the immunostimulatory viral antigenic proteins. These antigens, firstly encoded via the nucleic acid, can induce both humoral and cell-mediated immune reactions upon expression following cellular absorption. This type of vaccine has self-adjuvating attributes and hence can generate both adaptive (antigen-based) and innate immune reactions. In contrast, most other vaccine kinds require an adjuvant to attain a similar purpose. Nucleic acid-based anti-SARS-CoV-2 vaccines may have benefits over conventional vaccines such as (1) The great power of mRNA vaccines is able of producing potent antiviral neutralizing antibodies via triggering both CD4+and CD8+T-cells with only one or two low-dose vaccinations; (2) Due to its destruction procedure in cells, mRNA-based vaccines decrease the danger of infection and mutations are caused by insertion [117]. Vector vaccines can be widely divided into two categories: replication-incompetent vectors and replication-incompetent vectors vaccines. Replication-incompetent vectors show a big group of vaccines in expansion. This type of vaccine is usually based on another virus that has been designed to express the S protein and has been inactivated from reproduction in vivo via the elimination of sections of its genome. Replication-competent vectors are usually derived from weakened or vaccine strains of viruses that have been prepared to express a transgene, in this case, the S protein. Since viral vector vaccines lead to endogenous antigen generation, they are more likely to stimulate both humoral and cellular immune reactions. These vaccines can be advanced and generated rapidly on a wide-ranging and do not need extremely low temperatures for transport and storing. However, pre-existing immune reactions to the vector can restrict the capability of the vector to carry genetic material to target cells and thus decrease the efficiency of the vaccine [118–120]. Subunit vaccines are vaccines produced based on synthetic peptides or recombinant proteins. Dissimilar to inactivated or live-attenuated viruses and certain viral vectored vaccines, this vaccine kind mainly comprises particular viral antigenic parts; however, without containing each ingredient of infectious viruses, removing the worries of imperfect inactivation, improve pathogenicity, or pre-existing immune reaction. Like DNA or VLP-based vaccines, subunit vaccines are usually harmless without causing possible adverse immune reactions, making them hopeful vaccine candidates. Furthermore, subunit vaccines may target particular, well-defined neutralizing epitopes with enhanced immunogenicity and, or effectiveness. For example, Novavax has advanced and generated immunogenic virus-like NPs based on recombinant expression of the S-protein, while Clover Biopharmaceuticals is producing a subunit vaccine containing a trimerized SARS-CoV-2 S-protein utilizing their patented Trimer-Tag® method, though some full-length S-proteins for SARS as well cause enhanced infection and eosinophilic penetration [5, 121] (Table ​(Table22).

Table 2

Specifications of some SARS-CoV-2 vaccines in the advanced clinical development phase

Vaccine platform	Vaccine information	Developer	Phase and registered trials	Approved	Number of doses	Timing of doses	Clinical Trials.gov Identifier	Refs.
Inactivated vaccine	The inactivated COVID-19 vaccine (Sinovac: CoronaVac) with aluminum hydroxide	Sinovac	III 40 trials in 10 countries	56 countries	2	0, 28 days	NCT0445659	[168]
	Placebo/Aluminum Adjuvant of inactivated COVID-19 vaccine (Sinopharm (Beijing): Covilo vaccine (known as BBIBP-CorV (Vero Cells))	Beijing Institute of Biological Products/Sinopharm	III 38 trials in 16 countries	98 countries	2	0, 21 days	NCT04560881	[169]
Non-Replicating Viral Vector	Oxford/AstraZeneca: Vaxzevria (also known as AZD1222, ChAdOx1 nCoV-19)	University of Oxford/AstraZeneca	III 70 trials in 33 countries	148 countries	2	0, 28 days	NCT04516746	[170, 171]
	Adenovirus Type 26 vector (Janssen (Johnson & Johnson): Ad26.COV2.S and also known as Ad26COVS1, JNJ-78436735)	Janssen Pharmaceutical Companies	III 25 trials in 25 countries	113 countries	2	0, 56 days	NCT04908722	[172]
Protein Subunit	Novavax: Nuvaxovid (also known as NVX-CoV2373). Full length recombinant COVID-19 virus glycoprotein NP vaccine adjuvanted with Matrix-M1	Novavax	III 20 trials in 13 countries	39 countries	2	0, 21 days	NCT04611802	[173]
	National Vaccine and Serum Institute: Recombinant SARS-CoV-2 Vaccine (CHO Cell) (also known as recombinant COVID-19 Vaccine (CHO cell, NVSI-06–08). The adjuvanted recombinant protein (RBD-Dimer) expressed in CHO cells	National Vaccine and Serum Institute	III 3 trials in 2 countries	1 countries	2–3	0, 28, 56 days or 0+28 days	NCT05398848	[174]
RNA based vaccines	LNP-encapsulated mRNA vaccine (Moderna: Spikevax also known as mRNA-1273, and Elasomeran vaccine)	Moderna/NIAID	III 68 trials in 24 countries	88 countries	2	0, 28 days	NCT04470427	[175]
	3 LNP-mRNAs vaccine (Pfizer-BioNTech COVID-19 BNT162b2 Vaccine or Tozinameran)	BioNTech/Fosun Pharma/Pfizer	III 90 trials in 29 countries	148 countries	2	0, 28 days	NCT04848584	[176]
Virus-like particles	Medicago: Covifenz and also known as CoVLP, MT-2766, Plant-based VLP. Plant-derived VLP adjuvanted with AS03	Medicago Inc	III 6 trials in 6 countries	1	2	0, 21 days	NCT05040789	[177]

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Nanoparticle vaccines against SARS-CoV-2

Nanovaccinology has been used in preventive and remedial methods and can be utilized for each enhancement antigen processing or offering and, or as an immunostimulatory adjuvant [122]. Main NPs platforms contain lipid base NPs (LNPs) and VLPs. LNPs comprising ionizable lipids have been used widely to transport genetic compositions owing to their excellent loading valence, and excellent transfection performance VLPs are non-infected virus-mimicking particles created via the self-assembly of protein monomers combined with viral capsid proteins [123]. Furthermore, the general impression of “nanoimmunity via design” can assist us to create substances for immune regulation, either inducing or inhibiting the immune reaction, which would find usages in the vaccine production for COVID-19 or in neutralizing the cytokine storm, in order [124]. Animal trials helped the technological comprehension of how these novel kinds of nanovaccines work. Furthermore, some of these nanovaccines candidates have entered clinical studies next to the initial assessment in animal models, of which NPs based vaccines are hopeful vaccine candidates. The Moderna and Pfizer SARS-CoV-2 infection vaccines, more than 90% efficient against COVID-19 in humans, apply the mRNA to generate the viral S protein found on the surface of SARS-CoV-2 [125, 126].

Lipid-based nanoparticles vaccines

Conventionally, mRNA has not been utilized as a remedial factor since it is greatly unconstant and triggers the innate immune responses when administered. In addition, to enter the host cells, mRNA needs a delivery system to pass the cell membrane [127]. Moreover, the average half-life of mRNA vaccines reduces with enhancing temperature, which is a problem for their long time storing. However, chemical alteration by using an external covering of nonionic or an ionic surfactant improves the thermal constancy of mRNA. These chemical modifications alter the sizes of a NP and help in the efficient carrying of mRNA with greater thermal constancy [128]. Consequently, researchers are developing NPs delivery system that contains LNPs that entrap the mRNAs coding for the monoclonal antibody. This RNA-treatment method steadies the mRNA and can be administered recurrently, causing sustained generation of antibodies evading the efficacy of the innate immunity versus exogenous RNA. Additionally, the LNPs increase their mucosal and cellular absorption. Moreover, the positively charged LNP results in electrostatic absorbency to the negative charge of the mucosal membranes, decreasing their release via the mucosal cilia [127]. For example, Moderna’s mRNA vaccine is based on an LNP method [129]. This method was newly proceeded via Moderna to generate vaccine methods versus COVID-19 via utilizing mRNA-1273, encoding viral S protein [130]. BNT162b2 is the first vaccine based on the LNP-mRNA method and mRNA encoding the S protein locked in its pre-fusion structure [131]. In other investigations, mRNA (RNActive®) based vaccines (CVnCoV), include sequence optimum mRNA coding to a fixed shape of S protein entrapped in LNP. No vaccine-associated acute side effects were detected. Immune reactions, when evaluated as IgG antibodies versus S protein or its RBD via ELISA, and COVID-19 neutralizing antibodies (NAbs) evaluated via micro-neutralization, showed dose-affiliate enhancement. Primary outcomes demonstrated that CVnCoV is as well as safe and excellent tolerated in tested individuals, and is capable of enhancing the pre-existing immune reaction even at fewer dosage amounts [132]. Other studies, developed self-amplifying RNA (saRNA) entrapped in LNP as a vaccine. These vaccine immunizations stimulate a Th1 biased reaction in the mouse model, and there is no antibody-related increase detected. In addition, they identified significant cellular responses, as determined via IFN-γ generation, upon re-stimulation by COVID-19 peptides [133]. Uri Elia et al. developed an mRNA vaccine, based on LNPs-entrapped COVID-19 virus human Fc-combined RBD (RBD-hFc). Intramuscular injection of this vaccine induced a strong humoral reaction, a significant amount of NAbs, and a Th1-biased cellular reaction in the BALB/c mouse model [134]. LNP-based vaccines (NVP) co-encapsulated by antigens and monophosphoryl lipid A (MPLA, a potent TLR-4 agonist) were easily absorbed via DCs and increased DC maturation and antigen offering. Multilamellar vesicles were formed via hydrating a lipid film combined with DOPC, n-(Succinimidyloxy-glutaryl)-L-α-phosphatidylethanolamine, dioleoyl (DOPE-NHS) and MPLA (50:50:0.5 molar proportion). Mice vaccinated through RBD-NVP triggered strong and persistent antibody reactions versus RBD from COVID-19 [135]. In another investigation, researchers developed quick transformation of recombinant RBD into particulate formation by incorporating with liposomes comprising cobalt-porphyrin-phospholipid (CoPoP) strongly improves the functional antibody reaction. Compared to other vaccine preparations, immunization utilizing CoPoP liposomes incorporated with recombinant RBD induces several orders of magnitude greater rates of antibody titers in mice that inhibit pseudovirus cell entrance, prevent RBD interaction with ACE2, and suppress SARS-CoV-2 replication [136] (Table ​(Table3,3, Fig. 5).

Table 3

Some significant examples of NP-based vaccine candidates versus SARS-CoV-2

NPs types	Developer	Study stage	Description	Refs.
LNP	BioNTech/Fosun Pharma/Pfizer	Approved in 141 countries and 70 clinical trials in 26 countries	The quick and greatly scalable mRNA are generating and LNP design procedures enable the fast generation of several vaccine dosages	[175]
LNP	Moderna/NIAID	Approved in 85 countries and 56 clinical trials in 22 countries	Encapsulate mRNA vaccines in LNPs, may allow cytoplasmic transfer via fusogenic. It is possible that they used formulations of ionizable lipid, DSPC, cholesterol, and polyethylene glycol-lipid	[178, 179]
LNP	Fudan University/Shanghai Jointing, University/RNAcare, Biopharma	Animal experiments	LNP‐entrapped mRNA cocktail encoding VLP	[146]
Lipid-based	Park, et al	Animal experiments	NVP co-encapsulated with antigens and monophosphoryl lipid A was readily taken up via DCs and increased DC maturation and antigen offer	[135]
Ferritin-based VLP	Ma et al	Animal experiments	RBD and RBD-HR NPs vaccines induce more powerful NAb reactions and T lymphocyte immune reactions than monomers	[139]
Mesoporous silica NPs	N4 Pharma Plc	Cellular studies	Nuvec® carrying nucleic acids have irregular surfaces functionalized with polyethyleneimine, and may be beneficial in the race to develop a COVID-19 vaccine	[140]
AuNPs	Sekimukai, et al	Animal experiments	AuNPs, which are expected to act as an antigen delivery systems and an adjuvant in immunization, and TLR agonists, which have formerly been shown to be an efficient adjuvant in an ultraviolet‐inactivated SARS‐CoV-2 vaccine	[180]
Recombinant NP	Novavax	Approved in 36 countries and 15 clinical trials in 12 countries	NVX-CoV2373 is a recombinant NP vaccine created from the full-length, wild-type COVID-19 virus S protein. It is joined with a saponin-based Matrix-M adjuvant to increasing the immune reaction and generating great amounts of NAbs, which are fundamental in inhibiting the disease	[142]
1c-SApNP	Ufovax	Phase I clinical trial	Automatic-mount protein NPs vaccine method (1c-SApNP) prototype offerings sections of COVID-19 virus proteins that protrude from a scaffold of protein NPs, targeting to incite the immune reaction and incite the creation of antibodies to inhibit COVID-19	[149]

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Fig. 5

Several delivery methods for mRNA. LNPs are produced by the self-assembly of an ionizable cationic lipid. Various NPs of these cationic lipids (include 1,2-dioleoyloxy-3-trimethylammoniumpropane [DOTAP] or dioleoyl phosphatidylethanolamine [DOPE]) are prepared with subtle modifications (include cationic lipids+cholesterol NP, cationic lipids+cholesterol+PEG-LNP), where cholesterol and PEG-lipid are added to increase consistency. Other NP delivery systems include protamine (cationic peptide) nanoliposomes (sized approximately 100 nm), PEG-lipid functionalized dendrimer NPs (approximately 200 nm in size), positively charged oil-in-water (O/W) cationic nanoemulsion (approximately 120 nm in size), polyethyleneimine NP (approximately 100−300 nm in size), and cationic polymer (chitosan) NPs (approximately 300−600 nm in size)

Nanoparticles as a drug delivery system in SARS-CoV-2 infection

The nanocarrier of repurposed antiviral medicines can be improved by combining with cell-penetrating peptides (CPPs). CPPs transport the cargo within the cell either via macropinocytosis, caveolae-interceded endocytosis, or clathrin-free endocytosis manner. Therefore, the remedial use, of these CPPs should be fixed through the combination of multifunctional polymeric NPs or LNPs to increase selectivity, performance, and capacity of cargo delivery to prevent deactivation via proteases. So, nanoformulation-based CPP-encapsulated in NPs of repurposed antiviral medicines to treat SARS-CoV-2 infection. This method versus COVID-19 may be progressed and increased by conjugating it to the Tat-peptides via using nanoformulation-based NPs-delivery methods [143]. At present, siRNA treatment methods are inhibiting via the facility of siRNA enzymatic degradation, quick clearance, and lack of ability to pass into the cell membrane. However, these challenges can be notably addressed by utilizing NPs such as LNPs, polymeric NPs or their hybrid NPs, nanohydrogels, superparamagnetic iron-oxide NPs (SPIONs), and also functionalized AuNPs. PGA, poly(lactic acid) (PLA), polycaprolactone (PCL), and their copolymers PLGA have been accepted via FDA and more broadly utilized for in vivo siRNA transfer [144, 145]. As a result, the aerosol design for inhalation injection of designed siRNA NPs delivery system via measured-dosage inhaler is recommended as an effective way of an injection to the treatment of SARS-CoV-2 [146]. Inorganic polyphosphate (polyP), which was entrapped in silica/polyP NPs to inhibit polyP-destroying versus the alkaline phosphatase, was used to suppress connecting S protein to the ACE2 receptor in SARS-CoV-2. The result showed that completion of polyP might chip in improving the human innate immune responses in compromised, thrombocytopenic SARS-CoV-2 infected patients [147]. In other investigations, researchers developed recombinant DNase-1-covered PDA-poly(ethylene glycol) NPs (called long-acting DNase-1). The result showed that exogenously injected long-acting NPs DNase-1can efficiently decrease cell-free DNA (cfDNA) rates and neutrophil functions and may be utilized as powerful remedial intermediation for COVID-19. Researchers offered the remedial transport of a long-long-acting NP DNase-1 preparation for slowing the progress of sepsis in COVID-19 via inhibiting cfDNA [148].

Investigators have produced chitosan NPs for aerosol usage, which lets the adhesion and target delivery of medicines to the epithelial tissues of the lung and guarantees regulated discharge, thus decreasing the toxicity of the medications. Particular chitosan NP, named Novochizol, can entrapment of various medicines to deliver them to the lungs for the treatment of acute COVID-19 patients [149]. Other studies, used AgNPs, AuNPs, AgAu-NPs, and Pt NPs for delivery of the antiviral medicine, including hydroxychloroquine (HCQ), and chloroquine (CQ), to reduce the adverse events and increased the targeted therapy and efficacy of antiviral medications versus COVID-19 [150]. Moreover, dexamethasone encapsulated in NPs, and injecting it through intravenous or intranasal administration, can help to make better anti-SARS-CoV-2 therapy effect by targeting the strong corticosteroid medicine to hyper-triggered immune cells, with enhancing anti-edema acting and by eliciting its anti-fibrotic efficacy [151] (Table ​(Table44).

Nanoparticles as antiviral agents against SARS-CoV-2 Infection

In the absence of carrying additional medicine payloads, NPs can use specific mechanisms for direct viral inhibiting. One of these mechanisms is the degradation of viral protein structure. Biocompatible NPs can demonstrate a wide range of antiviral actions. The action of specific NPs, such as AgNPs and AuNPs, can chip in the generally antiviral function [152].

Quantum dots (QD), a kind of crystalline NPs, have great nano-based detecting, and they, can be utilized as antiviral remedies. Various metallic combinations (Pb, Cu, Ga, Zn, Hg) based on QD displayed target particular activities versus viral infection [153]. Moreover, QDs can be employed as ideal options versus pathogenic human CoVs diseases; For example, the antiviral actions of 7 diverse carbon QDs (CQDs) for remedying HCoV-229E infections were assessed [154, 155]. Moreover, the available documentation shows that NPs, including graphene, nanodiamonds, carbon nanotubes, and polystyrene particles, possess an inherent capability to trigger the immune system, related to their functionalization. For example, graphene oxide functionalized with amino groups (GO-NH2) stimulates the triggering of STAT1/IRF1 IFN signaling in monocytes and T lymphocytes, leading to the generation of T cell chemoattractant, and macrophage 1/Th1 polarization of the immune reaction, with slight toxicity. Significantly, hypericin graphene is on the list of computationally recognized potential therapy versus SARS-CoV-2. Besides, graphene is a potent immunomodulator, and GO-AgNPs increase the generation of natural antiviral protections (IFN-α and ISGs) [156]. Octadecylamine-functionalized and dexamethasone-incorporated nanodiamonds increase anti-inflammatory and pro-regenerative performance in human macrophages in vitro. A less amount of this NP also decreased macrophage penetration and expression of proinflammatory intermediary’s inducible nitric oxide synthase (iNOS) and TNF-alpha in mice. Generally, outcomes showed that nanodiamond particles could be beneficial as an intrinsically immunomodulatory system [124]. The usage of nitric oxide NPs (NONPs) can also be an option in the therapy of SARS-CoV-2 disease. An investigation by SARS-CoV-1 detected that NO suppresses viral reproduction via the cytotoxic response from intermediate factors, including peroxynitrite. Since COVID-19 infects endothelial cells, which are an origin of NO, carrying NO from NPs may be an alternative for NO substitution, also a reaction to the viral targeting endothelial cells. Furthermore, suppressing viral prevalence, NO can inhibit the beginning of inflammatory activities based on hypoxia-reoxygenation /ischemia–reperfusion, regulator the cytokine cascade, let the elimination of cell fragments, restrict lipid peroxidation and cell injury, decrease damaging vascular penetrability, and preserve sufficient blood circulation [149]. Carbon nanotubes (CNT) belong to the fullerene family (sized 10–100 nm). Investigators developed a new method against COVID-19 by acidizing, and RALyase modified CNTs in combination with photodynamic thermal efficacy [157]. In another investigation, researchers hypothesized that carbon dots (CDs) derived from Allium sativum (AS-CDs) may have the capability to downregulate the expression of proinflammatory cytokines and return the immunological abnormalities to normal in SARS-CoV-2 infection. CDs have now been investigated in the nanobiomedicine field as a hopeful theranostic candidates for bioimaging and medication/gene transfer. The antifibrotic and antioxidant properties of AS are explained with accuracy, as confirmed in numerous investigations. It is found that the most active constituent of AS, allicin has an extremely strong antioxidant and reactive oxygen species (ROS) scavenging efficacy [158].

ZnNPs have been offered favorable versus the SARS-CoV-2 by preventing the mucosal connecting of the virus, inhibiting the virus reproduction, IFN-γ/α production, triggering the enzymes involved in several cellular actions, and reducing the inflammatory reaction, or increasing the immune system of the host [155]. Other investigations, showed that Iron oxide NPs (IONPs) (Fe2O3 and Fe3O4) interact with the S1-RBD COVID-19. Fe3O4 created a more constant composite with S1-RBD. These interplays of IONPs are anticipated to be related to viral protein structural alterations, and therefore viral inhibition. Consequently, recommend FDA-accepted-IONPs proceed with SARS-CoV-2 therapy clinical trials. Combinations that interact with the S1-RBD are hypothesized to inhibit virus binding to host receptors and prevent viral infection [159]. AuNPs can be excellent alternatives for antiviral factors versus SARS-CoV-2 infection. The capability of AuNPs functionalized via diverse groups, including 3-mercaptoe-ethyl sulfonate (Mes), undecanesulfonic acid (Mus), octanethiol (Ot), and a novel peptide, to suppress COVID-19 was studied. The results showed that functionalized AuNPs have significant influences on the RBD and powerfully interact with the virus protein. In addition, the AuNP functionalized via a novel peptide creates a more constant compound with RBD in contrast with ACE2. AuNP-EG2, AuNP-Ot, and AuNP-Pep coat the entire connection surface of RBD of the COVID-19 [160].

Zhang, et al. developed 2 kinds of cellular nanosponges, which are prepared of the plasma membranes derivative from human lung epithelial kind II cells (Epithelial-NS) or human macrophages (MΦ-NS) for the therapy of SARS-CoV-2. The membranes were then covered onto polymeric NPs cores developed from PLGA by a sonication technique to create Epithelial-NS and MΦ-NS, in order. Cell membrane covering lets nanosponges receive the viral receptors associated with CoVs entrance in the target cells; however, it will be capable of inhibiting the chronic inflammation related to SARS-CoV-2 infection [161]. Cai, et al. developed photothermal NP that includes a semiconducting polymer core, (PCPDTBT), which combines NAbs connected on the surface of a photothermal NP to catch and deactivate SARS-CoV-2 actively. An amphiphilic polymer cover is applied to entrap the PCPDTBT core. The NP, a biocompatible polyethylene glycol surface, is functionalized by a monoclonal NAb particular to the S protein, which allows targeted and effective catching of virus with great composite affinity (0.07 nM), thus inhibiting the entrance of virus into target cells. As soon as stimulation via a 650-nm light-emitting diode (LED), which has a more favorable harmlessness method than traditional laser stimulation, the photothermal NPs per se deactivate the caught COVID-19 via heat [162]. A metal NP compound TPNT1 (comprising AuNPs, AgNPs, ZnONPs, and Clo2) was able to suppress 6 main sections of SARS-CoV-2 by efficient concentration within the limited area as food additives. TPNT1 was shown to inhibit viral entrance via preventing the connection of S proteins to the ACE2 receptor and interacting with the syncytium form. As TPNT1 is most efficient via previous incubation with viruses, one potential mechanism for the antiviral action of TPNT1 may be ascribable to bindings of virus surface glycoproteins with the metal NPs, and so inhibiting the virions from binding to target cells [163] (Table ​(Table44).

Conclusion

NPs can help to advance present treatments and as well be leveraged to generate new modalities which can destroy or prevent viruses via exclusive mechanisms of action. Based on their exclusive attributes, NPs have numerous specific benefits that can be leveraged to enhance the action of antiviral medicines. Payloads entrapped in NPs have less exposure to the exterior surroundings, which can help preserve them from systemic destruction while decreasing cytotoxicity. Moreover, NPs can increase the pharmacokinetic profiles of existing antiviral medicines via prolonging circulation time, binding particular tissue locations, and enhancing bioavailability. The efficiency of hydrophobic medications that are generally problematic to formulate and transport in vivo can be significantly improved by NPs. Owing to their perfect dimensions features and great surface area, NPs can associate with viruses in a multivalent method, allowing for extremely more powerful binding interactions. Generally, these developing therapeutics NPs are intrinsically resistant to viral mutations and can be used extensively versus a diversity of several viruses. NPs delivery methods contain antivirals, which can be produced from either synthetic or natural substances. Each one of these delivery methods has its collection of benefits and disadvantages for some uses. It is thus significant to choose the most suitable one and then improve its design. The SARS-CoV-2 pandemic continues to spread worldwide by an immediate requirement for a harmless and preservative vaccine to effectuate herd protection and regulate the spread of COVID-19. The rapid ratifications of mRNA1273 and BNT162b2 are significant achievements in the medication history. The NPs method can play a prime function in fighting SARS-CoV-2 using nanovaccines, which possess NPs and action as a delivery system of antigen that could trigger preservative immune responses. NPs have inherent immunomodulatory attributes that can affect the remedial act of vaccines. As the spread of viruses is faster than the development of effective vaccines, drug and vaccine studies should be complementary to what has already been achieved with previous CoV-related research.

Acknowledgements

Author contributions

Saman yasamineh: Writing – original draft. Pooneh Yasamineh: Writing – review & editing. Yalda Yazdani and Omid Gholizadeh: Writing – review & editing. Alireza Khanalipour farkhad: Writing – review & editing. Raheleh Tabatabaie: Writing – review & editing. Hamed Afkhami: Writing – review & editing. Fateme Davodabadi: Writing – review & editing. Hesam Ghafouri Kalajahi and Daryoush Pahlevan: Writing – review & editing. Akram Firouzi-Amandi: Writing – review & editing. Kazem Nejati-Koshki and Mehdi Dadashpour: Conceptualization, Supervision, Writing – review & editing. All authors participated in the manuscript in the critical review process of the manuscript. All authors read and approved the final manuscript.

Funding

Not applicable.

Availability of data and materials

Not applicable.

Declarations

Footnotes

Contributor Information

Kazem Nejati-Koshki, Email: ri.ca.smura@itajen.k.

Mehdi Dadashpour, Email: moc.liamg@0041idhemruophsadad.

References