Rhinovirus, an Age‐Old Problem Yet to be Solved: A Comprehensive Review Discussing Modern Therapeutics

ABSTRACT

Background and Aims

The human Rhinovirus, a positive‐sense, single‐stranded RNA virus within the Enterovirus genus of the Picornaviridae family, is the most prevalent viral pathogen in humans and the primary cause of the common cold (Verywell Health 2024). Virus‐host interactions, particularly receptor‐mediated adhesion, are pivotal in viral pathogenesis. Competitive inhibition and the use of anti‐adhesive agents have emerged as potential strategies to prevent viral docking. This study aims to explore the structural biology of rhinovirus receptors, specifically the canyon‐like depressions involved in host cell recognition, and investigate molecular approaches to minimize infection and reduce recovery time.

Methods

A comprehensive structural analysis of human Rhinovirus 14 was conducted, focusing on its unique surface depressions (canyons) surrounding the five‐fold axes. Literature was reviewed for monoclonal antibody interactions via hybridoma technology, as well as anti‐adhesive agents like alginic acid, gelatin, chitosan, and carboxymethyl cellulose. Molecular docking simulations were referenced to evaluate the potential of organic compounds to disrupt viral adhesion.

Results

The canyon regions on the viral capsid were confirmed as receptor‐binding sites that are structurally shielded from antibody access, allowing the virus to evade immune detection. Anti‐adhesive agents demonstrated theoretical efficacy in competitively inhibiting receptor‐ligand interactions at these sites. Monoclonal antibodies, while effective in certain contexts, showed limited access to conserved binding residues due to spatial constraints. Organic compounds with flexible conformational geometry showed potential in blocking receptor sites by steric hindrance.

Conclusion

The structural characteristics of human Rhinovirus 14 play a crucial role in immune evasion and receptor binding. While current treatments are limited by the virus's high mutation rate, anti‐adhesive strategies offer a promising avenue to inhibit early‐stage infection and reduce recovery time. Further experimental validation of these agents is necessary to develop effective antiviral therapeutics.

1. Introduction

The Rhinovirus is a positive‐sense, single‐stranded RNA virus belonging to the genus Enterovirus in the family Picornaviridae. Rhinovirus is the most common viral infectious agent in humans and is the predominant cause of common cold [1].

Rhinovirus can cause serious consequences in high‐risk groups such as the elderly, immunocompromised people, and those with chronic respiratory disorders. Approximately 17% of individuals hospitalized with rhinovirus infections develop severe respiratory problems [2]. It accounts for 50%–80% of asthma exacerbations and 20%–50% of COPD exacerbations [3, 4]. In Brazil, rhinovirus accounted for 30% of respiratory virus hospitalizations [5]. Although rarely lethal, its mortality rates are comparable to influenza and RSV [6], and higher in senior patients [7]. There have been fatal cases documented in blood/marrow transplant recipients and youngsters with bronchopulmonary dysplasia. Despite its benign appearance, rhinovirus can cause severe disease and death in susceptible individuals.

Depending on the serotype, rhinoviruses belonging to the Picornaviridae family infect respiratory epithelial cells by attaching to either LDLR or intercellular adhesion molecule‐1 (ICAM‐1) [8]. The virus's positive‐sense RNA genome is released into the cytoplasm by uncoating in endosomes following receptor‐mediated endocytosis [9]. Direct translation of the RNA results in a polyprotein, which is subsequently broken down into useful proteins for replication. Viral propagation and cell lysis are caused by the assembly of new virions in replication complexes. Asthma and COPD are exacerbated by this by inducing immunological reactions such as interferon release, cytokine production, and epithelial injury [3]. The main problem with viruses is their docking and their never‐ending mutational capabilities. As a result, despite such impressive scientific advances, a treatment for the flu that is effective in a short time span remains elusive and unknown.

This paper attempts to explore the aspects of viral receptors in human Rhinoviruses and ways of minimizing recovery time utilizing the properties of novel therapeutic approaches to overcome complications related to common cold during cases such as immuno‐suppression, pregnancy, or in neonatal health, specifically focussing on the attachment phase of the viral life cycle. A brief comparative study of the said approaches is also given on the basis of logistical issues and ease of commercialization.

1.1. General Information About the Virus

• i.The Rhinovirus: It is a positive‐sense, single‐stranded RNA virus belonging to the genus Enterovirus in the family Picornaviridae. Rhinoviruses have a single‐stranded positive‐sense RNA genome with a length between 7200 and 8500 nucleotides that directly serves as the mRNA for viral protein synthesis. At the 5' end of the genome is a virus‐encoded protein and, as in mammalian mRNA, there is a 3' poly‐A tail. Structural proteins are encoded in the 5' region of the genome while nonstructural genes are coded at the 3' end. This is the same for all picornaviruses. The viral particles themselves are not enveloped and have a dodecahedral capsid. The viral proteins are translated as a single long polypeptide, which is cleaved into the structural and nonstructural viral proteins [10], see Figure 1. Like other positive‐sense single‐stranded RNA viruses, rhinoviruses encode an RNA‐dependent RNA polymerase that lacks the ability to proofread and repair mismatches.

Figure 1.

Human Rhinovirus Genome organization, types of RVs and rhinovirus polyprotein structure.

The capsid consists of four structural proteins—VP1, VP2, VP3, and VP4—with VP1 mainly responsible for binding to the receptor ICAM‐1 on host cells, which starts the infection process. The viral RNA has a single open reading frame that codes for a polyprotein, which is subsequently cleaved by viral proteases into structural and nonstructural proteins. Although rhinoviruses do not have a lipid envelope, they are exceptionally stable in various environmental conditions. Their small size along with significant antigenic variability (over 150 serotypes) aids in their ability to evade the immune system and sustain high infection rates globally [11, 12] (Figure 1).

• ii.Mutational capabilities: The mutation rate has been estimated to range from 10⁻³ to 10⁻⁵ mutations per nucleotide per genome replication event. At ∼7200 nucleotides long, the rhinovirus genome would be expected to accumulate roughly one mutation per replication cycle [13]. The 3D‐polymerase of HRV lacks proofreading ability, leading to an estimated 1–4 mutations per replicative cycle. This contributes to the high genetic variability of rhinoviruses [14]. A single amino acid change in VP1 can render the virus resistant to antiviral compounds, demonstrating how mutations help the virus evade treatments [15]. Certain mutations enable rhinoviruses to switch receptor usage, allowing them to infect cells that lack their traditional receptors [16]. A mutation that replaces glutamate with valine in the VPg protein enhances replication [17], indicating how mutations can increase viral fitness [15]. Aspartate mutations in the 3C protease significantly impact enzymatic activity, influencing viral replication efficiency [18]. High mutation rates in rhinoviruses make vaccine development challenging due to continuous antigenic drift [19] (Figure 2a). For a brief overview of the general life cycle of the rhinovirus (Figure 2b).

Figure 2.

(a) Effects of mutational diversity on RVs, and increasing mutational rate in accordance with the Baltimore class of viruses. (b) Infection cycle of a typical rhinovirus.

1.2. Major Receptors of the Virus

There are 60 unique RV‐C (recently discovered RV [10]) spike proteins or fingers which are positioned on the surface of the virus at the protomer connections of VP‐1, VP‐2, and VP‐3, as well as caused by a VP‐1 loop insertion, in addition to the five‐fold plateau being noticeably reduced. The spikes are produced by specific residues on VP‐1 and VP‐2, and these surface elements are thought to be immunogenic [20, 21]. The majority of RV‐A types and all RV‐B types are recognized by the ICAM‐1 as their receptor [22, 23, 24]. Some of the major receptors and their functions are enlisted below, which are vital for RV attachment (Table 1, Figure 3).

Table 1.

Major receptors of the virus, their structure, function, and expression in different tissues.

Receptor	Structure	Function	Expression
ICAM‐1	The ICAM‐1 structure has five successively linked extracellular immunoglobulin domains, a carboxyl‐proximal trans‐membrane region and a short C‐terminal cytoplasmic domain ([104, 105], and [21]). The N‐terminal immunoglobulin domain (D1) is covered and captured during interactions with the Rhinovirus by a binding pocket composed of the VP‐1 and VP‐2 capsid proteins deep inside the canyon feature [21, 106]. The structure of ICAM‐1 is characterized by heavy glycosylation, and the protein's extracellular domain is composed of multiple loops created by disulfide bridges within the protein. The dominant secondary structure of the protein is the beta sheet, leading researchers to hypothesize the presence of dimerization domains within ICAM‐1 [107].	As a part of its normal cell functioning, ICAM‐1 is a costimulatory molecule for cell activation, and it helps to standardize and control the migration of leukocytes from blood to the tissues in inflammatory sites where it binds to two integrin receptors, leukocyte function‐associated antigen and macrophage‐1 antigen ([107, 108], and [21]). Fitting the mutICAM‐1 molecule into the density was simple and unique. It also would have been possible to fit domain D1 into the density when rotated by 180° relative to the best fit, but this would have placed D2 outside the electron density as a consequence of the 30° elbow angle [107]. The fit assumes that the elbow angle between the two domains is the same in the cryo‐EM reconstruction as in the crystal structure. This can be partly justified by observing the significant interactions between residues from the opposing domains, and by the fact that the fit is good, without involving additional conformational changes. In the model corresponding to the unique fit, the three loops BC, DE, and FG penetrate deep into the canyon (a surface depression into which the receptor binds [109]), consistent with mutational studies [54]. In addition, the short CD loop of ICAM‐1 lies against VP2 of HRV16 on the ‘south’ side of the canyon [107]. The footprint of ICAM‐1 onto the HRV16 surface is essentially as previously published [110], and there are extensive charge interactions between ICAM‐1 and HRV16 [107].	Typically expressed by epithelial cells, endothelial cells, and leukocytes when they are triggered by inflammatory stimuli or physical or chemical stress. IL13/T2 conditions decrease ICAM‐1 expression, reducing initial RV‐A16 attachment, while promoting replication post‐attachment. Enhancement of autophagy/mitophagy under T2‐conditions may contribute to this increase in replication, while only modestly increasing cell death [111].
CDHR‐3	CDHR‐3 possesses a trans‐membrane domain that enables it to cross cell membranes. The CDHR‐3 cytoplasmic tail aids in directing the cell's response to an RV‐C infection [21, 112]. With the aid of obligatory Ca2+ ions at the domain junctions [21, 113], the extracellular domains of CDHR‐3 organize themselves into a rigid, solid, linear rod. The sequence of CDHR‐3 suggests that this protein comprises six extracellular domains.	Protein modeling suggested that the first two extracellular domain repeats of CDHR‐3 are important for RV‐C to cell interactions. These most likely bind viruses in a location other than the diminished canyon, possibly even at the two‐fold axes, even though the precise contacts between CDHR‐3 and RV‐C have not yet been definitively mapped. Recent research on recombinant CDHR‐3 has demonstrated that RV‐C [21, 103] is in interaction with the first extracellular domain. The hydrophobic pocket is present in the VP‐1 of the RV‐C, but the pore is missing and the pocket cannot contain any recognized pocket factor [21, 114]. The “collapsed” form of the pocket is physically identical to the empty pockets seen in the RV‐B. Comparing the two human CDHR‐3 alleles, the rs6967330‐A42 allele, which codes for the Y529 protein variation, has a higher potential for RV‐C binding and cellular replication than the rs6967330‐G allele [21], which codes for the C529 protein variant [21, 115].	Although CDHR‐3's gene is abundantly expressed in the brain, fallopian tubes and cellular surface of airway epithelia, its natural function is, as of now, unknown [21, 116]). In all known human and animal genomes, the gene is maintained and kept with a high degree of sequence conservation ([117, 118], and [21]). The rs6967330‐A allele, as opposed to the rs6967330‐G variant, has been linked to greater levels of total CDHR‐3 protein expression on cell surfaces, which directly increases RV‐C binding and viral replication [21, 115, 119, 120].
LDLR	The LDLR family of glycoproteins includes at least three members that have the ability to bind with and internalize Rhinoviruses [121, 122]. These include the very‐low‐density lipoprotein receptor (VLDLR), the LDLR‐related protein (LRP), and the low‐density lipoprotein receptor (LDLR) [123]. The extracellular portions of this class of receptors exhibit a peculiar arrangement of several structural modules, such as YMTD spacer domains (b‐propeller modules) [121, 124], ligand‐binding repeats and epidermal growth factor precursor repeats [24, 121]. An extra O‐linked sugar domain is present in the LDLR and VLDLR receptors.	The cytoplasmic tails of members of the LDLR family include motifs that are used in signaling pathways to link with a range of cytoplasmic adapter and scaffold proteins [121, 125]. Two domains (D2 and D3) of VLDLR interact with VP‐1 residues at the top of the fivefold plateau of the virion icosahedron [21, 126] to start a Rhinovirus infection.	LDLR is widely expressed in hepatocytes, regulating cholesterol metabolism, and in vascular smooth muscle and endothelial cells, contributing to lipid uptake and vascular health [127]. It is found in macrophages (plaque formation), neurons and glial cells (cognitive function), and adrenal/gonadal cells (steroid synthesis). Intestinal epithelial cells use LDLR for cholesterol absorption, while cancer cells exploit it for lipid uptake, linking it to metabolism and disease progression [128, 129, 130, 131, 132, 133, 134, 135].

Figure 3.

Major rhinoviral receptors and potential rhinoviruses for these receptors.

2. Adaptive Strategies Against Rhinoviruses Attachment

Rhinoviruses are constantly mutating, making it difficult to produce anti‐adhesive medicines that are effective against new strains. However, recent research has focused on adaptive and broad‐spectrum anti‐adhesive medicines that can prevent rhinoviruses from adhering to host cells even as they change.

2.1. Dextran‐Based Self‐Degrading Anti‐Adhesive Agents

Various anti‐adhesive agents can be used, like polyethylene glycol (PEG), antibodies, proteoglycans, and peptide‐based inhibitors can also be used but their cost depends on various factors. These anti‐adhesive agents will actually block the viral binding site from attaching itself with the receptor by creating a thin barrier in the form of a binding site‐receptor interface.

Researchers from Japan's Advanced Institute of Science and Technology (JAIST) created LYDEX, a self‐degrading dextran‐based medicinal glue having anti‐adhesive, hemostatic, and sealing capabilities. This material is particularly promising for blocking viral adherence, including rhinoviruses, while allowing for natural decay after its job is complete.

2.1.1. Composition and Preparation

2.1.1.1. Aldehyde‐Functionalized Dextran (AD)

The backbone of LYDEX, dextran, is oxidized using sodium periodate to introduce aldehyde (─CHO) groups, resulting in AD. These groups make it possible for Schiff bases to form with polymers that include amino acids, which facilitates the development of hydrogel and crosslinking (JAIST, 2023) (Figure 3).

2.1.1.2. Succinic Anhydride‐Treated ε‐Poly‐L‐Lysine (SAPL)

When ε‐poly‐L‐lysine was treated with succinic anhydride at 50°C for an hour, leads to the formation of a poly‐ampholyte (polymers with both cationic and anionic functional groups) called SAPL or succinic anhydride‐treated ε‐poly‐L‐lysine. This component largely improves the flexibility, hydrophilicity, and bio‐degradability of the matrix of the hydrogel by adding carboxyl (─COOH) and amine (─NH2) groups. Since modification of succinic anhydride improves tissue adhesion and water solubility, SAPL plays a vital role in supporting LYDEX's property to act as a bio‐adhesive [25] (Figure 3).

The content of SAPL and the extent of oxidation of the dextran (20%–40%) were adjusted to maintain a balance between controlled biodegradation and mechanical integrity. Gel thickness, which affected the rate of degradation and the effectiveness of anti‐adhesion property, was crucial to its functional lifespan. The presence of Schiff base bonds was verified and confirmed using infrared (IR) and nuclear magnetic resonance spectroscopy, which also helped to monitor the hydrolysis of these bonds over time in normal physiological conditions.

2.1.1.3. Cross‐Linked Schiff Base Bonds (Imine Bonds, ─C═N─)

Schiff Base Bonds that are cross‐linked are reversible, dynamic covalent imine bonds (Imine Bonds, ─C═N─) that can break and reform in the presence of water, thus providing a promising approach to create a dynamic covalent system. These are created when the amine groups in SAPL react with the aldehyde groups from the oxidized dextran. LYDEX can degrade over time thanks to these linkages, which facilitate self‐degradation through hydrolysis and the Maillard reaction (Figure 3).

2.1.1.4. Water‐Based Hydrogel Network

This soft, flexible hydrogel adapts to tissues, lowers mechanical stress, and inhibits adhesions after surgery because the crosslinked polymer matrix holds onto water molecules.

2.1.1.5. Controlled Oxidation Levels (20%–40%)

The crosslink density, gel stiffness, and rate of degradation are all directly impacted by the level of dextran oxidation. Although they cause faster breakdown, higher oxidation levels can weaken adhesion (JAIST, 2023).

2.1.1.6. pH‐Sensitive and Biodegradable

LYDEX is completely bioabsorbable without leaving any harmful residues after undergoing enzymatic and pH‐dependent breakdown. Comparing it to traditional adhesives, studies show that it is highly biocompatible and has low cytotoxicity.

By creating a transient hydrogel barrier that stops undesired tissue connections, LYDEX, a self‐degradable dextran‐based anti‐adhesive substance, was created to treat postsurgical adhesions. Its production is largely dependent on the generation of Schiff bases, in which oxidized dextran (AD), produced by oxidation of sodium periodate, combines with ε‐poly‐l‐lysine (SAPL) treated with succinic anhydride to form a cross‐linked hydrogel network [25]. Dynamic covalent imine bonds produced by this Schiff base formation allow controlled breakdown via hydrolysis and molecular scission brought on by the Maillard reaction (JAIST, 2023).

Effective anti‐adhesion capabilities were exhibited by LYDEX, both in vitro and in vivo, in rabbit colon models. Depending on its composition, it gradually degraded over a period of 5–8 days. LYDEX was safer than conventional adhesion barriers like Seprafilm since it demonstrated low cytotoxicity, minimum immunological response, and great biocompatibility in contrast to synthetic adhesives. Due to its flexible nature, the hydrogel was successful in adapting to tissue surfaces easily, lowering mechanical stress and allowing fibrosis‐free repair. For wider clinical applications, additional modification is necessary due to issues like susceptibility to moist surgical settings, possible inflammatory consequences from the Maillard process, and unpredictability in degradation rates (Figure 4).

Figure 4.

Preparation of LYDEX—a biodegradable adhesive.

2.1.2. Mechanism of Action

• LYDEX's adaptive anti‐adhesive mechanism can be used to counteract rhinovirus mutations by dynamically blocking viral docking sites. Unlike static anti‐adhesives, LYDEX ensures that viruses cannot develop resistance.

• Static anti‐adhesives usually bind to specific viral proteins, as VP1 in rhinoviruses. If the virus mutates this protein, the anti‐adhesive is rendered ineffective.

• LYDEX, on the other hand, operates differently: it creates a transient hydrogel barrier that physically prevents viral attachment rather than depending on a single molecular contact.

• Because LYDEX does not directly target viral proteins, viruses cannot rapidly develop resistance via point changes in surface proteins. Traditional anti‐adhesives remain unaltered over time, allowing viruses to gradually adapt and evolve escape mutations.

• LYDEX degrades via the Maillard reaction, resulting in a constantly changing structure that viruses find difficult to detect or adapt to. By the time a virus could acquire resistance, the glue had already broken down, requiring the virus to restart its evolution with each exposure [26] (Figure 5).

Figure 5.

Mechanism of action of LYDEX and overview of the Maillard reaction.

2.1.3. Complications

• 1.Since the self‐degradable nature of LYDEX depends on variables including aldehyde concentration, oxidation level, and film thickness, one major problem is uneven degradation. Its capacity to prevent adhesion may be impacted by this fluctuation, which could result in erratic absorption rates in vivo.
• 2.Furthermore, Schiff base bond breakdown may result in inflammatory responses and minor tissue irritation due to Maillard reaction byproducts. In addition, the study emphasizes how excessive gel thickness might delay degradation and raise the possibility of localized fibrotic reactions.
• 3.In addition, even though LYDEX has low cytotoxicity, some people may experience tissue hypersensitivity with extended exposure. To guarantee controlled degradation and minimal immune response in medical applications, the findings highlight the necessity for additional improvement.
• 4.Since LYDEX requires precision hydrogel synthesis and controlled degradation mechanisms, its production might involve higher initial costs. If LYDEX is intended for medical applications (e.g., as a tissue adhesive or anti‐adhesive coating), regulatory approvals (e.g., FDA, EMA) will add to the overall cost. If LYDEX enters mass production, the cost could decrease due to economies of scale (95).

2.1.4. Ways to Overcome the Limitations

To ensure that LYDEX degrades at a uniform pace and in a controlled manner, researchers can adjust the concentration of aldehyde and cross‐linking techniques. More sophisticated fabrication techniques, such as creation of hydrogel layer‐by‐layer, micro‐patterning, facilitate uniform thickness, consistent degradation rate, and uniform degradation rate and radial symmetry. Customized and replicated degradation behavior is further automated by predictive computational modeling.

To diminish the immune and inflammatory responses triggered by the breakdown byproducts, adding antioxidant compounds or switching to bio‐linkers or enzyme‐sensitive linkers can be effective. Safety is something that requires long‐term animal studies across varying profiles of patients. Increasing the thickness of LYDEX layers may delay the pace of degradation and increase the possibility of fibrosis. Bio‐printing in 3D, dual‐phase systems (faster breakdown of outer layers), are effective at maintaining balance between form and safety.

2.2. Nano Anti‐Virals

2.2.1. Composition/Method of Preparation

Metal‐based nanoparticles like silver (Ag), zinc (Zn), copper (Cu), and their oxides, as well as carbon‐based nanomaterials like graphene oxide, are commonly used to make nano‐antivirals. Through processes like the production of reactive oxygen species (ROS), denaturation of viral proteins, and suppression of viral replication, these nanoparticles demonstrate antiviral qualities. The preparation techniques include physical deposition (e.g., magnetron sputtering for metallic coatings), sol‐gel synthesis (for metal oxides), and chemical reduction (e.g., reduction of silver nitrate with sodium borohydride). In addition, certain nano‐antivirals are made by direct adsorption onto substrates like glass or textiles or by layer‐by‐layer deposition of polyelectrolytes. Strong adherence and long‐lasting virucidal effects are guaranteed by these coatings, which can be applied by brushing, spraying, dip‐coating, or sono‐chemical deposition. The other types of nanoparticles available are shown in Figure 6.

Figure 6.

Varieties of nanoparticles in antiviral drug delivery.

2.2.2. Mechanism of Action

2.2.2.1. Direct Interaction With Viral Particle Surface Binding

To stop viruses from entering host cells, metallic nanoparticles (such as copper and silver) bind to viral surface proteins like gp120 in HIV or spike proteins in coronaviruses.

2.2.2.2. Peptidoglycan Bond Disruption

By rupturing peptidoglycan bonds, certain nanoparticles—particularly copper and silver—can cause structural disintegration and disturb viral envelope structures.

2.2.2.3. ROS Generation

ROS, such as hydrogen peroxide (H2O₂), hydroxyl radicals (OH⁻), and superoxide anions (O₂⁻), are produced by nanoparticles, particularly metal oxides (ZnO, CuO, and TiO₂). ROS hinder viral proliferation and infectivity by destroying viral proteins and nucleic acids (RNA/DNA).

2.2.2.4. Nano‐Antivirals' Inhibition of Viral Attachment and Entry

The capacity of nano‐antivirals to stop viral attachment and entrance into host cells is one of their most important processes. To prevent viral infections before they have a chance to replicate and spread, this step is essential. Silver nanoparticles (AgNPs), zinc nanoparticles (ZnNPs), and other metallic nanoparticles interact with host cell receptors and viral surface proteins to mainly block viral entrance.

2.2.3. Silver Nanoparticles (AgNPs) and Viral Entry Inhibition

Silver nano‐particles are one of the most researched nano‐antivirals because of their high affinity for viral surface proteins. Their mode of action mainly involves:

• Attaching to the viral surface protein: AgNPs communicate with important glyco‐proteins present on the viral envelope, including spike protein (S‐protein) in SARS‐CoV‐2 and gp120 in HIV. In the case of coronaviruses, this binding inhibits the virus‐host attachment by preventing the virus from identifying and connecting to host cell receptors such as ACE2 (angiotensin‐converting enzyme 2). According to a study on SARS‐CoV‐2, AgNPs bind to the viral spike protein's 394‐glutamine residue and stops it from interacting with ACE2 [27].

• Viral envelope structural disruption: Viral proteins undergo structural changes and also face oxidative stress due to silver nano‐particles, rendering them nonfunctional. This prevents the infection by inhibiting the virus from merging with the membrane of the host cell.

• Inhibition dependent on size: Because of their increased surface contact, smaller AgNPs (about 10 nm in diameter) have been reported to have a higher binding affinity for viral proteins. Because they are less likely to bind with the viral surface proteins, larger nanoparticles (> 40 nm) exhibit decreased efficiency [27].

• Viruses and electrostatic interaction: Silver nanoparticles can be designed to have positive surface charges, but the envelopes of many viruses, such as herpes and influenza, have negative charges. By improving their contact with viral proteins, this electrostatic attraction prevents the virus from infecting the host cell.

2.2.4. ZnNPs and Viral Entry Inhibition

ZnNPs also have a significant function in preventing viral attachment by targeting glycoproteins on the viral envelope. Their mechanism consists of:

• Direct binding to viral glycoproteins

Zinc ions attach to the histidine residues found in viral envelope glycoproteins. This connection interferes with viral docking processes, especially in viruses such as influenza, SARS‐CoV, and rhinoviruses.

• Inhibition of receptor‐mediated endocytosis: Numerous viruses, including SARS‐CoV‐2 and Semliki Forest Virus, gain entry into host cells through endocytosis. ZnNPs hinder this mechanism by inhibiting glycoprotein E1, which is essential for viral fusion with the host cell membrane [27].

• Zinc as a cofactor for antiviral proteins: Zinc serves as an important element of zinc‐finger antiviral proteins (ZAPs), which break down viral RNA and stop replication. The presence of ZnNPs boosts this innate antiviral defensemechanism [27].

• Inhibition of ACE2‐spike protein interaction in SARS‐CoV‐2: Like silver, ZnNPs can interfere with the interaction between the SARS‐CoV‐2 spike protein and ACE2 receptors. This blocks viral docking on human cells, thereby decreasing infection rates [27].

• Enhancement of host immune response: Nanoparticles, particularly those of silver, gold, and zinc, can stimulate immune cells by activating cytokine production. They induce an immune response that aids in viral/clearance while reducing inflammatory damage [27].

• Structural disruption and enzymatic inhibition: Copper and silver nanoparticles cause cross‐linking and degradation of viral genomes (DNA/RNA), leading to irreversible damage. Nanoparticles like graphene oxide and carbon nanotubes physically disrupt viral envelopes and capsids due to their sharp edges and strong adsorption properties [27].

2.2.5. Limitations of Nano‐Antivirals

• The major concern is to maintain the proper size and shape of mono‐dispersed NPs with stability during synthesis [28].

• NPs may accumulate in different bio‐organs, which may cause problems in normal biological functioning in the future [29].

• Since NPs may escape the immune challenge of the body, they may cause some sort of inflammation or toxicity [30].

• NPs can generate ROS, which are major contributors of inflammation, oxidative stress, and apoptosis.

• Still, there are many other disadvantages in using NPs. For example, toxicity, environmental harm, and organ damage may be caused by nano‐particles [30].

• Nanoparticles, after a threshold limit, may be toxic in nature and have to be degraded chemically.

• Some identified toxic mechanisms are through the production of ROS, which is cytotoxic, genotoxic, and neurotoxic, also. Those toxic effects of nanoparticles' depends on its type, size, surface area, shape, aspect ratio, surface coating, crystallinity, dissolution and agglomeration properties. Therefore, it is important to consider of any toxic effects of nanoparticles when it is being synthesized [31, 32].

2.2.6. Strategies to Overcome Nano‐Antiviral Limitations

For effective and lasting use of nano‐antivirals, systems for production need to be economical, environmentally friendly, and scalable, such as continuously feeding plants into reactors [33]. Functioning at the nano‐scale, filamentous viruses and nano‐particled therapeutics can greatly benefit from stability imparted by coatings and smart delivery systems as these enhancements make less medication necessary. Uniform safety criteria during health crises will allow faster approval of therapeutics. Meeting eco‐friendly goals needs responsible waste controls, the use of biodegradable materials and, in parallel, fostering trust with the public through education. Access to funding and infrastructure alongside the equitable distribution to integrate nano‐antivirals into healthcare deepens their reliability as an aid against viral outbreak.

2.3. Cationized Cellulose Nanocrystals (CNCs) for Virus Capture and Gene Delivery (Figure 7)

Figure 7.

Cationized cellulose nanocrystals (CNCs) for virus capture and gene delivery.

2.3.1. Composition

The researchers used surface‐initiated atom transfer radical polymerization (SI‐ATRP) of poly(DMAEMA) followed by quaternization with methyl iodide to make permanently cationic CNCs (CNC‐g‐P[QDMAEMA]). Key characteristics of cationized CNCs: Surface charge modification: Pristine CNCs had a negative zeta potential (−41 mV), whereas CNC‐g‐P(QDMAEMA) had a positive zeta potential (+38 mV), indicating successful cationization. Polymer grafting resulted in an increase in hydrodynamic size from 93 nm (pristine CNCs) to 202 nm (cationic CNCs), as evidenced by dynamic light scattering (DLS). Dispersion stability: Atomic force microscopy and transmission electron microscopy (TEM) revealed well‐dispersed rod‐like particles, indicating effective surface functionalization.

2.3.2. Method of Preparation

• Base material: CNCs are derived from cellulose, which is typically obtained from wood pulp or cotton fibers via an acid hydrolysis process.

• Surface functionalization: The CNCs undergo modifications with cationic polymer brushes to improve their virus‐binding capacity. This enhancement is accomplished through SI‐ATRP.

• Polymer used: The polymer brushes consist of quaternizedpoly(2‐dimethylaminoethyl methacrylate) (qPDMAEMA).

2.3.2.1. Modification Steps

• Surface activation: Initially, CNCs are functionalized with an initiator for ATRP.

• Polymer grafting: The cationic polymer is directly polymerized onto the CNC surface utilizing ATRP.

• Quaternization: The polymer chains undergo chemical modification to introduce permanent positive charges, which are crucial for virus binding.

2.3.3. Mechanism of Action

• Electrostatic interactions: The positively charged qPDMAEMA brushes exhibit strong interactions with the negatively charged viral capsid of the rhinovirus. This interaction inhibits the virus from adhering to its natural receptor on host cells.

• Multivalent binding: The extensive surface area of CNCs, coupled with the dense polymer brushes, facilitates multiple binding sites for the virus, thereby enhancing their antiviral efficacy.

• Physical barrier effect: The CNCs establish a protective layer that obstructs viral particles from connecting to epithelial cell receptors.

• Nontoxic binding mechanism: In contrast to chemical antivirals, this approach does not compromise the structural integrity of the virus but instead hinders its binding and entry into host cells.

  The interaction between CNC‐g‐P(QDMAEMA) and viruses was investigated using DLS, gel electrophoresis, and TEM.

• Binding to CCMV (icosahedral plant virus):‐

• 1.In pure water, CCMV measured 27 nm, however after mixing with CNC‐g‐P(QDMAEMA), free CCMV was no longer detectable at a CNC concentration of 1.6 mg/L.
• 2.The virus and CNCs created secondary assemblies (~500 nm in size), and larger CNC concentrations resulted in aggregation, generating micron‐sized structures.
• 3.Gel electrophoresis demonstrated the production of stable virus‐CNC complexes, which moved through the gel before being completely arrested at high CNC concentrations. The electrostatic interaction mechanism could be used in surface coatings to trap viruses, preventing infections [34, 35].

2.3.4. Limitation of the Proposed Method

The logistical limitations of cationic polymer brush‐modified CNCs for antiviral applications arise from challenges in scalability, stability, cost, safety, and regulatory approval. The complex and multi‐step synthesis process, particularly surface‐initiated ATRP, renders large‐scale production both costly and difficult to standardize. Inconsistencies in raw material purification and polymer grafting further obstruct reproducibility. Stability concerns, including aggregation, degradation, and limited shelf life, diminish their long‐term effectiveness, while elevated production costs—attributable to the expense of polymer precursors and purification processes—impede commercial viability. Safety apprehensions emerge from the potential cytotoxic effects of cationic polymers and unclear long‐term health implications in human applications. Furthermore, regulatory challenges, which encompass rigorous safety and environmental impact evaluations, prolong approval timelines. Tackling these issues necessitates cost‐effective synthesis techniques, improved stabilization strategies, comprehensive biocompatibility assessments, and scalable production models.

2.3.5. Ways to Overcome the Limitations

While cationic polymer brush‐modified CNCs demonstrate potential for antiviral applications, considerable logistical challenges persist. Addressing these issues will necessitate:

• 1.More economical synthesis methods (e.g., alternative polymerization techniques).
• 2.Improved stability strategies to avert aggregation and degradation.
• 3.Thorough biocompatibility and environmental impact assessments for regulatory approval.
• 4.Pilot production and industry collaborations to increase manufacturing capacity while lowering costs.

2.4. pH‐Responsive Polymers With Anti‐Adhesive and Antiviral Properties

By preventing viral adherence, permitting regulated antiviral release, and improving targeted medication delivery, pH‐responsive polymers can successfully fight rhinoviruses. pH‐sensitive polymer coatings can change surface charges at physiological pH (~6.5–7.5) to break the bond between rhinoviruses and epithelial cell ICAM‐1 receptors. Furthermore, polymer‐based antiviral carriers can be activated by the somewhat acidic environment (~6.2–6.5) of the nasal cavity, guaranteeing regulated release of lactoferrin, zinc oxide, or silver nanoparticles at infection sites.

2.4.1. Composition/Mode of Preparation

The synthesis of pH‐responsive polymers entails several stages, contingent upon the type of polymer, its intended application, and the method of drug incorporation. Generally, these polymers are produced through free radical polymerization, emulsion polymerization, or grafting techniques to include functional groups that react to pH fluctuations. For example, methacrylate‐based polymers (such as Eudragit) are produced via solution polymerization and subsequently processed into nanoparticles, hydrogels, or coatings. Polysaccharide‐based pH‐sensitive polymers, including chitosan and fucoidan, are frequently fabricated through ionic gelation or chemical crosslinking with pH‐sensitive agents. Electrospinning is routinely employed to create pH‐responsive nanofibers that regulate drug release, while self‐assembled polymeric micelles are formed through solvent evaporation or nanoprecipitation to encapsulate antiviral medications for targeted delivery. To guarantee stability, these polymers are subjected to freeze‐drying, spray‐drying, or lyophilization before their formulation into intranasal sprays, inhalers, or antiviral coatings [36, 37, 38, 39, 40].

2.4.2. Mechanism of Action in Antiviral Applications

pH‐responsive polymers operate by altering their charge, solubility, or swelling characteristics in response to variations in environmental pH, thus facilitating targeted antiviral effects. In the context of rhinovirus inhibition, polymeric coatings applied to surfaces or masks modify their surface charge at physiological pH (~7.0), thereby obstructing viral attachment to host epithelial cells. Mucoadhesive polymers (e.g., chitosan) expand in the mildly acidic environment of the nasal cavity (~6.2–6.5), systematically releasing antiviral agents (such as lactoferrin, silver nanoparticles, or zinc oxide) at the site of infection. In drug delivery systems, nanoparticles or hydrogel carriers maintain stability at neutral pH but either dissolve or expand at acidic pH, guaranteeing localized release of the drug within inflamed tissues. This targeted mechanism improves bioavailability, reduces systemic side effects, and extends the duration of drug action, rendering pH‐responsive polymers exceptionally effective in the prevention of rhinovirus and in respiratory antiviral treatments [41, 42, 43, 44, 45].

For targeted treatment, polysaccharides with pH‐dependent swelling and mucoadhesive qualities, such as chitosan and fucoidan, can be added to intranasal sprays or antiviral inhalers. These polymers can also be utilized in coatings and self‐cleaning antiviral masks that, when exposed to respiratory droplets, kill rhinoviruses. The potential of pH‐responsive polymers for antiviral applications, specifically in drug delivery, coatings, and biomedical materials, is being investigated in a number of recent studies. Amorphous polymeric nanoparticles with pH‐responsive characteristics were studied by Naik et al. [46] to improve the bioavailability of antiviral medications by increasing their solubility. For the sustained release of the antiviral medication favipiravir, which exhibits prolonged activity, Zaman et al. [47] created hydrogel‐based pH‐sensitive carriers. In their study of pH‐responsive electrospunnanofibers, Schoeller et al. [48] showed how well these nanofibers can carry antiviral drugs like acyclovir under controlled conditions (Taylor & Francis).

Using pH‐sensitive peptides targeting the H1N1 influenza virus, Liang et al. [49] investigated inhalable dry powder formulations with potential uses in rhinovirus‐targeted nasal sprays. In addition, Singh and Nayak [50] reviewed pH‐responsive polymers for drug delivery, emphasizing their potential for antiviral treatments. These studies highlight the growing interest in smart, pH‐sensitive antiviral therapies, paving the way for next‐generation drug delivery systems and self‐sterilizing surfaces.

2.4.3. Factors Affecting the Commercial Viabilities of pH‐Responsive Polymers

A number of variables, including market demand, scalability, cost‐effectiveness, and regulatory approvals, affect the commercial viability of pH‐responsive polymers in antiviral applications. These polymers could be used by businesses who invest in self‐sterilizing surfaces, biodegradable coatings, and nasal sprays to prevent COVID‐19, influenza, and rhinovirus. Scaling up manufacturing, guaranteeing formulation stability over the long term, and obtaining FDA or EMA approval for consumer and medical applications are all obstacles, too. Cost‐effective synthesis techniques and integration with the biomedical and pharmaceutical industries will be key to future success.

2.4.4. Companies Working on pH‐Responsive Polymers

pH‐responsive polymers for antiviral drug delivery and coatings are being actively developed by a number of biotech and pharmaceutical companies, with an emphasis on mucosal protection, self‐sterilizing surfaces, and controlled drug release. While Ashland Global Holdings (USA) is developing pH‐sensitive hydrogels and mucoadhesive polymers for mucosal barriers, Evonik Industries (Germany)is using Eudragit polymers for targeted antiviral medication formulations. Polymun Scientific (Austria) is researching lipid‐based pH‐responsive drug carriers for antiviral applications, whereas Lubrizol Life Science (USA) is creating smart polymer coatings with possible antiviral qualities. While NanoViricides Inc. (USA) focuses on antiviral treatments based on nanopolymers that may incorporate pH‐sensitive medication release mechanisms, Biomer Technology Ltd. is concentrated on self‐sterilizing coatings to stop viral adherence.

Likewise, there are other adaptive anti‐adhesive solutions, currently under research, that, if commercialized, can help a large section of society bypass immuno‐complications and provide a remedy for Rhinoviral and other chronic respiratory diseases.

2.5. Recent Studies on Monoclonal Antibody (mAb) Therapy Against Rhinovirus Attachment

mAbs are a type of immunotherapy that can be used to treat a variety of diseases, including viral infections. mAbs are made by genetically engineering cells to produce antibodies that target specific antigens on the surface of viruses or cells, and consequently, can be used to inhibit rhino viral infection in a variety of ways. One such way is to block the binding of the virus to its receptor. For example, a mAb that binds to the ICAM‐1 receptor can prevent rhinovirus from binding to it and entering the cell. Another way to inhibit rhinoviral infection with mAbs is to interfere with the virus's ability to replicate. For example, a mAb that binds to the VP‐1 protein can prevent the virus from uncoating and releasing its genetic material into the cell [51].

Recent investigations into mAb therapy targeting rhinovirus attachment underscore its promise in obstructing viral entry and averting infections. Research conducted by Smith and Baker [52] and Tomassini and Colonno [53] illustrated that mAbs such as Fab17‐IA could neutralize human rhinovirus 14 (HRV‐14) and inhibit ICAM‐1 interactions, which are crucial for viral attachment. Additional research by Abraham and Colonno [54] and Colonno et al. [55] demonstrated that anti‐receptor mAbs could displace bound virus particles and obstruct internalization. Privolizzi et al. [56] investigated prophylactic antibodies aimed at virion stabilization and entry inhibition, while Ku et al. [57] identified neutralizing mAbs directed at the VP1 GH loop, effectively preventing viral attachment. Parray et al. [58] examined the potential of inhalable mAbs for respiratory infections, and Behzadi et al. [59] developed a cross‐reactive mAb that stimulates phagocytosis against rhinovirus. These discoveries highlight the increasing interest in mAb‐based antiviral therapies, paving the path for focused, nontoxic treatments against rhinovirus infections.

2.5.1. Composition

mAbs used in rhinovirus treatment are typically humanized or totally human IgG antibodies that target viral surface proteins or host cell receptors (such as ICAM‐1) to prevent viral attachment and invasion. Their makeup contains the following components.

2.5.1.1. Immunoglobulin Structure

The bulk of mAbs utilized in antiviral therapy are of the IgGisotype, specifically IgG1 or IgG4. They are made up of two heavy chains (~50 kDa) and two light chains (~25 kDa), forming a Y‐shaped structure that binds viral epitopes with excellent specificity [60] (see Figure 7).

2.5.1.2. Variable and Constant Regions

The Fab region (fragment antigen‐binding) contains hypervariable complementarity‐determining regions that recognize viral capsid proteins such as VP1, VP2, or VP3. The Fc region interacts with immune effector cells (e.g., macrophages, NK cells) to trigger antibody‐dependent cellular phagocytosis (ADCP) and other immune responses [61].

2.5.1.3. Humanized or Fully Human Antibodies

Originally, mAbs were derived from murine sources, but modern therapeutic approaches use humanized (chimeric) or fully human mAbs to reduce immunogenicity and enhance efficacy. Humanized mAbs, such as Fab17‐IA, contain mouse‐derived variable regions grafted onto a human IgG framework [62].

2.5.1.4. Antigen Targets

Certain mAbs target viral capsid proteins (e.g., VP1 GH loop) to block viral attachment to epithelial cells. Other antibodies bind ICAM‐1, the primary host receptor for major group rhinoviruses, preventing viral docking and entry [63].

2.5.1.5. Modified Forms

Multivalent Fab fragments (lacking Fc regions) are designed for improved penetration into mucosal tissues, including intranasal formulations. PEGylatedmAbs (chemically modified with PEG) provide increased stability and prolonged bioavailability for extended therapeutic effects [64].

2.5.2. Mechanism of Action of mAbs in Rhinoviral Therapy

mAbs employed in rhinoviral therapy operate by inhibiting viral attachment, neutralizing viral particles, enhancing immune clearance, and augmenting mucosal immunity. Rhinoviruses predominantly gain entry into human epithelial cells by attaching to ICAM‐1 receptors. Anti‐ICAM‐1 mAbs, including Mab 1A6 and CFY196, obstruct this interaction by occupying the receptor sites or inducing conformational alterations in ICAM‐1, thereby incapacitating its function [65]. Moreover, certain mAb fragments (Fab‐based mAbs) bind competitively to rhinovirus capsid proteins, such as VP1, VP2, and VP3, obstructing virus‐cell interactions and preventing initial attachment in Figure 8.

Figure 8.

Inhibition of the viral particle using Anti‐Icam1 monoclonal antibodies like Mab1A6 and CFY196.

The neutralization of viral particles represents another essential mechanism, during which mAbs identify specific epitopes on the rhinovirus capsid and form antigen‐antibody complexes. This binding renders the virus noninfectious by obstructing the release of viral RNA into the host cell, ultimately halting viral replication before it commences. This neutralization guarantees that the virus cannot commandeer the host's cellular machinery for replication, thereby diminishing viral load and the severity of the infection.

In addition to direct viral neutralization, mAbs also promote immune system clearance through interactions with immune effector cells. mAbs possessing an intact Fc region engage Fc receptors on macrophages and natural killer (NK) cells to facilitate ADCP, whereby macrophages absorb and degrade virus‐bound antibodies. Furthermore, complement activation may be initiated, leading to the lysis of virus‐infected cells, while antibody‐dependent cellular cytotoxicity empowers NK cells to identify and eliminate infected cells, thus preventing further viral dissemination.

Another merit of mAb therapy is its capability to enhance mucosal immunity, particularly in the upper respiratory tract, where rhinoviruses primarily replicate. Intranasal mAbs establish a protective barrier on the nasal mucosa, averting viral spread to deeper lung tissues. Certain inhalable mAbs are designed to bind to mucus layers, ensuring prolonged antiviral activity at the site of infection. This localized strategy minimizes systemic side effects while preserving high efficacy.

In summary, mAbs provide a highly specific and focused antiviral strategy by preventing rhinovirus attachment, neutralizing viral particles, and engaging the immune system for viral clearance. Their capacity to be administered through intranasal or inhalable formulations further enhances their potential for preventing and treating rhinovirus infections. These mechanisms render mAbs a promising alternative to traditional antiviral medications, establishing a pathway for future prophylactic and therapeutic strategies against rhinovirus infections. Ongoing research and clinical trials continue to refine these therapies, optimizing their stability, efficacy, and commercial viability for widespread application in respiratory viral infections [65].

2.5.3. Limitations of This Method

Despite the encouraging prospects of mAb therapy in targeting rhinovirus attachment, numerous logistical limitations impede its widespread implementation. High production costs stemming from intricate biotechnological processes, such as cell culture, purification, and formulation, render large‐scale manufacturing financially burdensome. Batch‐to‐batch variability during mAb production can influence efficacy and consistency, necessitating rigorous quality control and regulatory compliance. The short half‐life of certain mAbs calls for frequent dosing, which elevates treatment burden and costs. Storage and stability issues, especially for intranasal or inhalable formulations, demand cold‐chain logistics, thereby restricting accessibility in low‐resource environments. Regulatory approval tends to be slow, as comprehensive clinical trials are required to verify safety and efficacy before commercialization. Moreover, limited market demand for rhinovirus‐specific mAbs in comparison to other more life‐threatening infections diminishes the attractiveness of investment for pharmaceutical companies. Lastly, public perception and adoption challenges emerge, since patients and healthcare providers may prefer traditional antivirals over innovative mAb‐based therapies. Tackling these obstacles demands cost‐effective production strategies, enhanced stability, streamlined regulatory pathways, and increased awareness of mAb advantages in the treatment of rhinovirus infections.

2.5.4. Methods to Overcome the Limitations

Cost‐effective methods like cell‐free expression systems and enhanced bioreactors need to be integrated to bypass the logistical challenges of producing rhinovirus mAb therapies [66]. Creation of biosimilars adds greater value by increasing the availability of more inexpensive alternatives to branded biologics. Enhanced PEGylation and nonspecific Fc modifications allow for greater mAb retention in the circulation, which subsequently reduces the need for frequent dosing. Lyophilization and formulation into thermostable variants reduce the need for cold‐chain storage, thus improving shelf‐life and distribution, particularly in under‐resourced settings [67]. Alternative and expedited regulatory routes like adaptive clinical trials can also shorten approval timelines [68]. In addition, enhanced economic support from public‐private partnerships boosts overall funding, while public education campaigns and integration into respiratory treatment pathways increase the use of mAbs as an alternative to traditional antiviral therapies [69].

2.6. VP1 and VP2 Denaturation for Rhinovirus Inactivation

Denaturation is the process of unfolding or breaking down the secondary and tertiary structures of these proteins. This can be caused by a variety of factors, including heat, chemical, and radiation [70]. Denaturation of VP‐1 and VP‐2 can disrupt the structure of the capsid, making it unable to attach to cells or deliver the genome. This can prevent the virus from infecting cells and causing disease. Denaturation of VP‐1 and VP‐2 can also be used to inactivate the virus. This can be done by heating the virus to a high temperature or by exposing it to chemicals or radiation. Inactivated viruses cannot infect cells and cause disease.

2.6.1. Methods Used for VP1 and VP2 Denaturation in Rhinovirus Inactivation

The denaturation of VP1 and VP2, which are the principal capsid proteins of rhinoviruses, is being investigated through thermal, chemical, and electromagnetic techniques aimed at viral inactivation. Heat treatment conducted at designated temperatures has been demonstrated to induce capsid destabilization, rendering the virus noninfectious. Methods involving electromagnetic radiation, such as ultraviolet (UV) light and radiofrequency radiation, are also under examination for their capacity to compromise capsid integrity. The use of chemical denaturation through agents such as sodium hypochlorite has been considered as a method for modifying protein structure, which results in viral inactivation. Research conducted by Bjorndahl [71] and Ylihärsilä [72] provides evidence that structural modifications of VP1, VP2, and VP3 can inhibit viral entry. Recent studies by Zhu [73] have revealed that exposure to radiofrequency disrupted VP1‐host receptor interactions, whereas Sanglay [74] established that electron beam irradiation and chemical treatments led to capsid degradation.

2.6.2. Mechanism of Action of Electromagnetic Denaturation

The fundamental mechanism for electromagnetic denaturation is based on disrupting the secondary and tertiary protein structures of VP1 and VP2, which are required for capsid integrity and host adhesion. Heat denaturation ruptures hydrogen bonds, causing capsid deformation [75]. UV and radiofrequency radiation cause molecular excitation, resulting in structural instability and preventing the virus from binding to host receptors [76]. Electron beam irradiation and chemical exposure change protein cross‐links, lowering capsid stiffness and preventing viral genome release into host cells [77]. When the capsid integrity is disrupted, the rhinovirus loses its capacity to infect host cells, effectively eliminating its replication capability.

2.6.3. Limitations and Ways to Overcome Them

Despite its intriguing potential, electromagnetic denaturation confronts various obstacles, including inefficiency at low doses, potential capsid repair mechanisms, and safety issues for human applications [78, 79]. UV light has low penetration, making it difficult to achieve total viral inactivation on surfaces and aerosols [80]. Furthermore, chemical denaturation agents may pose toxicity hazards or leave dangerous residues, limiting their safe use in human contexts [81]. To address these constraints, integrated techniques such as combining UV exposure with antiviral coatings or air filtration devices can improve overall efficacy [82]. Furthermore, optimizing parameters such as exposure time, intensity, and wavelength is critical for attaining safe and efficient viral inactivation, especially for commercial and large‐scale application. Current research efforts are aimed at improving electromagnetic and chemical exposure parameters such that they are scalable, cost‐effective, and appropriate for clinical and public health applications [83].

3. Comparative Study of the Above Methods

Different antiviral and anti‐adhesive strategies differ in their mechanism, effectiveness, specificity, stability, safety, cost, regulatory feasibility, and commercial viability. Dextran‐based self‐degrading anti‐adhesive agents inhibit viral adhesion by creating a temporary barrier, but their effectiveness is moderate and they require controlled degradation to prevent inflammation. Nano antivirals aim directly at viruses and show high effectiveness yet encounter concerns regarding toxicity and elevated production costs. Cationized CNCs capture viruses and facilitate gene therapies, presenting high specificity, stability, and biodegradability at a reduced cost, thus becoming commercially viable for applications in coatings and air filtration. pH‐responsive polymers alter charge at particular pH levels, ensuring targeted drug release, high stability, and biodegradability, making them appropriate for self‐sterilizing surfaces and nasal sprays. mAbs represent the most effective and precise option, directly preventing viral entry, but they carry high costs, complex regulatory processes, and stability issues, constraining mass production. VP1 and VP2 denaturation compromises viral capsid integrity, hindering infection, but safety risks and scalability difficulties obstruct commercialization. While mAbs are the top choice for targeted treatment, CNCs and pH‐responsive polymers provide the greatest commercial potential owing to their cost‐effectiveness, scalability, and wide applicability in antiviral coatings, textiles, and drug delivery systems.

3.1. Best Possible Therapies

The optimal therapy relies on the purpose and practicality:

• For immediate medical applications: mAb therapy stands out as the most efficient choice since it directly neutralizes the virus, hinders attachment, and has demonstrated clinical success. Nevertheless, its high costs and prolonged regulatory approval process reduce its viability for large‐scale applications.

• For preventative and non‐therapeuticnontherapeutic applications: pH‐responsive polymers present a flexible solution for nasal sprays, antiviral coatings, and self‐sterilizing materials. Their excellent stability, biocompatibility, and straightforward production make them well‐suited for broad utilization in infection prevention.

• For combination therapies: Cationized CNCs offer an effective strategy by capturing viruses and facilitating gene therapy, which could be paired with mAbs or nano‐antivirals for improved protection.

4. Medical Complications Related to Rhinovirus Infection

4.1. Rhinovirus and Auto‐Immune Disorders

Rhinovirus, the major cause of the common cold, has been linked to the development and exacerbation of autoimmune illnesses. It can operate as an environmental trigger, causing immunological dysregulation in genetically predisposed people. Studies have found correlations between rhinovirus infections and the onset or exacerbation of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and dermatomyositis. The virus is also thought to play a role in chronic inflammatory airway illnesses such as asthma and chronic rhinosinusitis, which have immune system dysfunctions similar to autoimmune diseases.

Locatello et al. [84] investigated how rhinoviruses cause chronic rhinosinusitis and its links to autoimmune illnesses such as asthma and allergic rhinitis. According to the study, chronic rhinovirus infections may cause persistent inflammation, resulting in immunological dysregulation [84]. Jayaraman et al. investigated how rhinovirus A peptides could activate immunological responses associated with anti‐melanoma differentiation‐associated protein 5 (MDA5) dermatomyositis. This study supports the hypothesis that viral infections can cause muscle and skin autoimmune disorders [85]. McCreary et al. [86] described a case of Acute Respiratory Distress Syndrome associated with Adult‐Onset Still's Disease, in which rhinovirus was discovered. The study emphasizes the possible significance of viral infections in worsening autoimmune lung diseases [86]. Choy et al. [87] discovered that FUT2 gene variations affect rhinovirus‐related COPD exacerbations. The study links rhinovirus infections to immunological dysfunction in lung illnesses, which may include autoimmune components. Merrion et al. [88] analyzed cases of parvovirus B19 and rhinovirus infections in patients with red cell diseases, implying that viral co‐infections may worsen immune‐related hematologic illnesses. Degaetano et al. [89] reported a case where rhinovirus‐induced multifocal pneumonia led to secondary autoimmune complications. This suggests that respiratory viral infections could contribute to immune‐mediated lung diseases. AlQahtani et al. [90] observed that hematopoietic stem cell transplant recipients with rhinovirus infections developed febrile neutropenia and viral pneumonia, showing how viral infections can complicate immune recovery in autoimmune patients (AlQahtani et al.).

Following the studies mentioned, a novel and holistic approach is to use something that prevents the viral docking at the first instance, like using some self‐degrading anti‐adhesive agents, which might as well be immunostimulant.

4.1.1. Inosine Pranobex

Inosine pranobex is an immunomodulatory and antiviral drug that has demonstrated efficacy against various viral infections, including those caused by rhinoviruses. It has dual immunomodulatory and antiviral characteristics, increasing T‐cell activity, NK cell function, and cytokine secretion, all of which improve the immune system's ability to battle viral infections [91]. Furthermore, it can prevent viral reproduction in infected cells, making it effective against a variety of RNA and DNA viruses [92].

Several studies have demonstrated its efficacy in treating common respiratory infections, including those caused by rhinoviruses.

• Campoli‐Richards et al. [93] reviewed clinical trials showing inosine pranobex reducing the severity and duration of rhinovirus infections by stimulating immune responses.

• Beran et al. [94] conducted a Phase 4 study, confirming that inosine pranobex was safe and effective for treating patients with acute respiratory viral infections, with quicker recovery times.

• Sliva et al. [95] emphasized its role in reducing viral load and immune suppression, making it particularly beneficial for individuals with weakened immunity.

Long‐term use has been evaluated in immune‐compromised patients, showing no significant adverse effects or toxicity concerns [96]. As of 2024, the global inosine pranobex market is valued at approximately USD 0.21 billion and is projected to reach USD 0.25 billion by 2032, growing at a compound annual growth rate of 2.2% (Business Research Insights, 2024).

4.1.2. Global Companies Selling Inosine Prenobex

• 1.“Isoprinosine, a treatment extensively used for antiviral therapies, is produced by Newport Pharmaceuticals Ltd (Ireland) which has positioned itself as a leading global producer of Isoprinosine.” (Newport Pharmaceuticals Ltd. (2024). Isoprinosine: A global leader in antiviral treatment. Retrieved from https://www.newportpharma.com).
• 2.“Viatris Inc. (USA) is the supplier of generic inosine pranobex in a number of markets.”
• 3.“Teva Pharmaceuticals (Israel) specializes in the development of low‐cost generic antivirals.” (Teva Pharmaceuticals Ltd. (2024). Affordable generic antiviral medications and immune‐modulating therapies. Retrieved from https://www.tevapharm.com).
• 4.“Sanofi S.A. (France) has researched pranobex of inosine in immunosuppressive therapy.” (Sanofi S.A. [2024]. Research on pranobex of inosine defending and supporting the immune system. Retrieved from: https://www.sanofi.com).
• 5.“Adamed Pharma S.A. (Poland) is known for the marketing of Groprinosin which contains Inosine Pranobex and is used extensively in Eastern Europe.” (Adamed Pharma S.A. [2024]. Groprinosin: Inosine Pranobex for immune defense and antiviral uses. Retrieved from https://www.adamed.com).
• 6.“Gedeon Richter Plc. (Hungary) produces Inosine pranobex for the markets of Eastern Europe and the CIS.” (Gedeon Richter Plc. [2024]. Manufacture of Inosine pranobex for Eastern European markets. Retrieved from: https://www.gedeonrichter.com).
• 7.“Abbott Laboratories (USA) research active formulation and marketing therapeutics which Inosine pranobex is an immune booster.” (Abbott Laboratories. (2024). Research works on as an immune booster. Retrieved from: https://www.abbott.com).

4.2. Rhinovirus and Pregnancy Related Complications

Rhinovirus, recognized as the primary contributor to the common cold, is typically considered mild; however, it may present risks during pregnancy, particularly in severe instances. Although it is not usually fatal, complications such as pneumonia, respiratory failure, sepsis, preterm labor, and fetal distress may occur, especially in women with existing conditions like asthma or heart disease [97]. Recent advancements in the management of rhinovirus‐related complications highlight the importance of early detection, enhanced supportive care (including high‐flow nasal cannula oxygen therapy), and multidisciplinary treatment strategies; nevertheless, no specific antiviral medications or vaccines are currently available for rhinovirus prevention during pregnancy. While certain respiratory viruses, such as RSV [98] have now been authorized for vaccination in pregnant women [99], there is no comparable solution provided for rhinovirus. Research indicates that ovulation may enhance ICAM‐1 and LDLR receptor expression in ovarian tissues, receptors that rhinoviruses utilize for cellular entry [100]; however, there is no definitive evidence establishing a correlation between this increase and heightened systemic vulnerability to infection. Should rhinovirus disseminate to the uterus, the increased receptor expression could theoretically enable viral attachment, yet no targeted medications presently exist to safely inhibit this process during pregnancy. Although experimental antiviral compounds like IMP‐1088 [101] and pleconaril [102] have been investigated, their safety for pregnant women has not been demonstrated. In light of these constraints, preventative strategies such as rigorous hygiene practices, avoidance of contact with infected individuals, and the preservation of immune health remain the most effective safeguards against rhinovirus during pregnancy.

5. Conclusion

To conclude, there is ongoing research even for very basic viral illnesses but complete and ideal solutions to any disease caused by them are still not known. In addition to antiviral drugs, there are a number of other strategies that can be used to inhibit rhinovirus replication. These methods include competitive inhibition, use of mAbs, use of anti‐adhesives to block viral docking and denaturing VP‐1 and VP‐2 proteins in the viral canyon structures, thereby preventing binding of host receptors to the virus. Therefore, it has been found that employing said methods and further applying them in advancing medicine and technology will eventually give us a more effective and rapid treatment for the common illnesses caused by Rhinoviruses. With continued research, it is hoped that new and better treatments for the common cold will be developed in the future.

Author Contributions

Srinjoy Maitra: conceptualization, methodology, software, formal analysis, data curation, writing – original draft; validation, investigation, writing – review and editing. Jenifer Rajak: conceptualization, formal analysis, software, methodology, writing – review and editing, writing – original draft, validation, investigation, data curation. Agnik Ghoshal: methodology, writing – original draft, software, data curation, formal analysis, investigation, conceptualization, validation. Bedaprana Roy: supervision, writing – review and editing, investigation, software, conceptualization. Shoham Ghosh: investigation, formal analysis, supervision, methodology, software. Arup Kumar Mitra: resources, project administration, validation, visualization, conceptualization, supervision. Ajoy Kumer: software, methodology, conceptualization, data curation, supervision, resources, project administration, writing – review and editing, funding acquisition. Bikram Dhara: conceptualization, investigation, writing – review and editing, methodology, software, project administration, supervision, resources, visualization, validation, formal analysis, data curation.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

The lead author Ajoy Kumer, Bikram Dhara affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Data Availability Statement

All authors have read and approved the final version of the manuscript [Ajoy Kumer] had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. The [Ajoy Kumer] affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. The sources of data used for the preparation of the manuscript have been mentioned in the references. No new data generated for this manuscript.