In recent times, the rapid advancement of nanomaterials has significantly transformed various scientific domains such as aeronautics, military applications, and medicine. This progress has led to improved drug availability, precise delivery at cellular and intracellular levels, and minimized adverse effects, thereby enhancing therapeutic effectiveness through nanotechnology. Nanomedicine can also address the advantageous medication resistance observed in viral therapy.

Nanoparticles (NPs) exhibit distinct physicochemical traits that demonstrate virucidal activity. Their small size, extensive surface area, targeted action, and responsive properties make them efficient antiviral agents. Studies have shown inactivity of viruses like H1N1, H5N1 influenza [9] , poliovirus [10] , NIPAH, respiratory syncytial virus, herpes simplex, human papillomavirus, Dengue, and lentivirus when exposed to NPs. Nanomaterials like AuNPs, through infrared light emissions, can bind to and disrupt the structure of coronaviruses, effectively killing the virus. Beyond their direct antiviral effects, NPs are seen as potential carriers for antiviral medications, especially since specific antiviral therapies for many viruses remain limited [11] [12] .

Specifically targeting viral genes like SiRNA, microRNA, and shRNA as novel therapeutic agents against viruses like COVID-19 is being explored [13] [14] [15] . The proposed drugs such as Remdesivir and hydroxychloroquine might be co-encapsulated in mice using Nanocarriers to treat COVID-19. Additionally, the development of self-assembly protein nanoparticles (SANPs), a new nanostructure generated by the oligomerization of monomeric protectins via recombination technologies, shows promise in medicinal applications. SANPs ranging from 20 - 100 nm have potential in creating respiratory virus nanovaccines [16] . Researchers have developed nucleoprotein-based SANPs from the respiratory syncytial virus (RSV) and studied their potential as an antigenic vaccine in the RSV model [16] .

The utilization of SiRNA therapy offers several advantages compared to conventional medications and vaccines. Employing smaller amounts of siRNA to diminish viral RNA proves to be an effective strategy in preventing RNA viral replication. Insights gained from SARS-CoV studies can be extrapolated to SARS CoV-2, exhibiting high nucleic acid homology. Researchers have identified the efficacy of RNAi against the SARS-CoV virus, utilizing siRNAs from a plasmid to target specific regions of the viral genome. This discovery holds promise for a new era of antiviral medications to combat SARS [17] [18] .

Recent investigations have pinpointed the S generation in the SARS-CoV virus, associated with severe respiratory disease, as a viable target. Scientists have demonstrated that the S-section effectively inhibits viral infection and replication, suggesting its potential as a treatment option [19] [20] . In the context of COVID-19, a distinct strain of the MERS-CoV coronavirus, RNAi may play a transformative role. Researchers have identified specific siRNAs, Smad7-1 and Smad7-2, that exhibit potential in gene therapy utilizing RNAi to eliminate MERS-CoV in human lung and kidney cell lines, effectively suppressing viral replication and infection [19] [20] .

SiRNA antivirals may be applied selectively to cells lacking adequate endosomal release. Various nanocarriers composed of polymers, lipids, hybrid (polymer/lipid) NP, Nanochrome, silica, dendrimers, iron oxide NPs, and AuNPs are potential candidates for delivering targeted siRNA. FDA-approved materials like poly (lactic acid), polycaprolactone, poly[glycolic acid], and their copolymers have been authorized for tailored in vivo siRNA delivery. Additionally, NP configurations such as solid-lipid NPs, nanocarriers, nanostructured lipids, and liposomes are suitable for advancing SiRNA delivery systems. Cationic lipids or polymers maintain low endosomal pH, enhancing proton and water influx, leading to endosomal rupture and subsequent release of bound siRNA into the cytoplasm. Nanotechnology-based structures can facilitate SiRNA loading for inhalation and pulmonary delivery via aerolite-based systems. The incorporation of antibodies targeting alveoli-specific surface markers-I and II shows promise for nanocarrier functionality and targeted delivery to lung cells and other tissues expressing these therapeutic siRNA indicators [21] [22] .

DNA and mRNA vaccines are currently under investigation in the context of the COVID-19 pandemic. The CD8+ cytotoxic T cell responses triggered by DNA vaccines play a crucial role in eliminating the virus. In vitro transcription mutation vaccines offer a potential solution to cell requirements and associated regulatory hurdles. Notably, DNA vaccines demonstrate greater longevity compared to mRNA vaccines; while mRNA is non-integrating and doesn’t pose a risk of insertion mutations, DNA vaccines provide more enduring protection. Modifications can be made to mRNA, altering its half-life, stability, and immunogenicity. For instance, research at the Imperial College of London and by Arcturus Therapeutics involves incorporating self-amplifying RNA to prolong the otherwise short half-life of RNA and boost S protein production [23] [24] [25] .

The Moderna mRNA vaccine employs nanoparticles with a lipid platform, although several other nucleic acid delivery nanotechnologies are in development. Nanotechnology platforms such as cationic nanoemulsions, liposomes, dendrimers, or polysaccharides have been utilized to enhance the stability and distribution of mRNA-based vaccines. These platforms hold promise for improving the nuclear translocation of plasmid DNA [26] .

Vaccines derived from SARS and MERS proved to be more prone to infection-related antibody enhancement (ADE) compared to other vaccinations. This susceptibility stems from the full-length S protein’s wide array of potent epitopes, triggering diverse antimicrobial and cellular responses. However, this broad reaction spectrum might pose an increased risk of adverse effects on the immune system’s ability to combat the disease [27] [28] [29] . As antibodies that don’t neutralize SARS-CoV-2 infections and potentially life-threatening allergic inflammations are on the rise, the La Jolla Institute of Immunology (LJI), funded by the National Health Institutes (NIH), has initiated efforts in this domain. In silico analysis has unveiled various protein B- and T-cell epitopes, and LJI is pioneering a peptide epitope vaccination that holds promise for more efficacious antigens in second-generation SARS vaccines [30] [31] [32] [33] [34] .

Peptide-based vaccines represent the simplest, swiftly validated, and rapidly producible vaccine format. These can be formulated as peptides or blends, delivered with suitable nanocarriers, or encoded within nucleic acid vaccine formulations. Industry and academic institutions are leveraging predicted B- and T-cell epitopes in their SARS-CoV-2 subunit vaccines, such as OncoGen and the University of Cambridge/DIOSypVax, utilizing immunoinformatic sequences from the S-protein [35] [36] [37] .

Nanoparticles offer potential in targeting lymph nodes (LNs) or subcellular subsets and locations. The “albumin hitchhiking” strategy exploits LNs’ natural transportation capability via albumin. Nanoparticles have been instrumental in designing dual-targeted hepatitis B virus (HBV) vaccines, directing them towards specific lentil-resident dendritic cell and macrophage subsets. This targeting led to enhanced viral clearance in chronic HBV mice models [38] . Nanotechnologies are also employed for various vaccination and therapeutic purposes, generating VLPs from mammalian viruses, insect viruses, plant viruses, and bacteriophages (Figure 1(a) and Figure 1(b)). VLPs mimic infection-associated molecular patterns, triggering robust antigen-specific immune responses. Their visualization and administration systems serve as potent adjuvant systems, activating and amplifying immune responses [39] .

The design features of vaccines, such as encapsulated antigens versus surface-displayed antigens, dictate antigen processing and presentation, influencing the ensuing immunological response. Nano-barriers like polymeric micelles (PEG-PE) alter antigenic peptides’ structure, enabling cytosolic transport for LN targeting, APC absorption, and antigene cross-presentation (Figure 1(c)). A

well-developed delivery framework is crucial for combatting future waves of SARS-CoV-2 and other emerging viruses effectively and efficiently [40] .

Immunotherapy utilizing Nanoparticles (NPs) has proven highly effective in managing infectious diseases. Nonetheless, improving treatment efficacy while minimizing adverse effects remains challenging. Understanding the immune system’s response to infections and exploring potential methods for immune modulation are crucial steps in developing successful immunological treatments. Recent studies have revealed that pathogen-associated molecular patterns (PAMPs) on the virus’s surface alert innate immune cells upon encountering the first line of immune defense (such as mucus and ciliated cells). This triggers the release of type I interferons (IFN-α/β), heightening the risk of complications [41] [42] [43] . Subsequently, other immune cells like natural killer cells, alveolar macrophages, monocytes, and neutrophils become activated during acute infections, leading to the production of pro-inflammatory cytokines that affect respiratory epithelial cells. IFN-I halts viral reproduction via various pathways, contributing to cell cytotoxicity. While anti-PAMP injections may cause pulmonary complications in some individuals, this remains unclear in humans. SARS-CoV-2 infection has been associated with prolonged antibody production and decreased CD4+/CD8+ T cells. Macrophages and dendritic cells play pivotal roles in initiating specialized immune responses, retracting virus particles via phagocytosis, initiating IFN-I production, and triggering the adaptive immune response [45] [46] .

Studies suggest that pretreatment with IFN-α may induce the development of IFN genes and signaling pathways pre-SARS-CoV infection. Early data suggest that IFN-1 exhibits antiviral activity against SARS-CoV-2, but further clinical studies are required to confirm these findings. Antibodies mediate the death of infected cells through various pathways like phagocytosis, neutralization, complement system activation, and antibody-related cell cytotoxicity. Regulating the virus’s pathogenicity and the host’s immune response is crucial to effectively combat viral infections [47] [48] .

Monoclonal antibodies’ use stands out among other techniques due to their specificity, minimal risk of bloodborne pathogens, and safety. They can be more effectively used in recovered patients than in new cases [49] [50] [51] [52] . IFNs combat infections by inducing antiviral protein production and cytokine-stimulated interferon genes, exerting antiviral effects by halting replication or aiding the immune system’s adaptability. IL-6 is considered crucial in treating SARS-CoV-2 due to its association with heightened inflammatory cytokine levels [53] [54] [55] [56] [57] . Implementing these outlined immunotherapy techniques, independently or in combination with other medications, has been suggested for SARS-CoV-2-infected patients. However, the manufacturing of monoclonal antibodies remains challenging, expensive, and time-consuming, requiring sophisticated infrastructure and components for cost-effective and timely immunotherapy [58] [59] [60] .

Nanoparticles can influence the immune system’s performance through various means such as enhancing multivalent receptor linkages, controlling intracellular processes, facilitating cytosolic transport, targeting the innate immune system, and reducing immune modulator toxicity. They can also integrate multiple antigens on their surface to more effectively activate the immune system [61] [62] [63] (Figure 2).

Development of vaccines

The immunization system, owing to its innate capability to induce a durable protective immune response, stands as one of the most efficient public health measures in preventing or curbing the spread of infectious diseases. Vaccines consist of two critical elements: the antigen, eliciting the immune response, and the adjuvant, which modulates or enhances the immune response to the antigen [64] . Various vaccine formulations have elicited immune responses against infectious diseases. Live Attenuated or Inactivated Entire Pathogen Vaccines have been extensively utilized to control human and animal diseases. However, safety

concerns such as genetic reversion and potential tumorigenicity in immunocompromised hosts exist with attenuated vaccines. Not all pathogens can be employed as live vaccines due to their virulence or inherent immunity. DNA or RNA vaccines, the latest in vaccination, come with drawbacks like inadequate antigen immunogenicity, the need for adjuvants to bolster immune responses, and susceptibility to premature antigen breakdown in adverse conditions. Synthetic peptides, inactivated toxins, and recombinant subunit protein vaccines serve as alternatives to live-attenuated or inactivated vaccines, although evidence indicates their limited availability in the market [65] [66] [67] .

Vaccines are preferred over chemotherapeutic drugs in combating infectious diseases due to their specificity and capacity to induce an immune response [68] . Many current vaccines utilize viral proteins to achieve CoV neutralization. Antibodies generated target CoV proteins like M, E, or S, hindering viral entry by binding to these proteins [69] . Nano-based therapies have emerged as potential options against various forms of CoVs due to the immunostimulatory effects of NPs.