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Virus-like particle

Virus-like particles (VLPs) are non-infectious, self-assembling nanostructures composed of one or more viral structural proteins that mimic the organization, conformation, size, and symmetry of native viruses but lack any viral genetic material, rendering them incapable of replication or causing disease.^[1] These multiprotein assemblies typically range from 20 to 500 nm in diameter and can adopt various shapes, including icosahedral, helical, spherical, or rod-like forms, depending on the originating virus.^[2] First constructed in 1982 through recombinant expression of viral genes, VLPs have since been developed from over 110 viruses across 35 families, leveraging their biocompatibility, stability, and ability to elicit strong immune responses without adjuvants.^[2] VLPs are produced using a variety of heterologous expression systems, including prokaryotic hosts like Escherichia coli and eukaryotic systems such as yeast (Saccharomyces cerevisiae and Pichia pastoris), insect cells (via baculovirus vectors), mammalian cells, and even plant-based platforms, which enable scalable manufacturing and post-translational modifications essential for proper assembly.^[1] Self-assembly occurs spontaneously or is facilitated by scaffolding proteins, nucleic acids, or environmental cues during expression, resulting in particles that closely resemble authentic viral capsids in antigenic structure and cellular tropism.^[2] Classified into non-enveloped, enveloped, and chimeric types, VLPs can incorporate lipids or foreign antigens to enhance functionality, making them versatile tools beyond mere structural mimicry.^[1] The primary applications of VLPs lie in vaccinology, where they serve as safe, immunogenic platforms for prophylactic vaccines; notable FDA-approved examples include hepatitis B virus (HBV) vaccines like Engerix-B (approved 1989), which provide long-term immunity (up to 30 years) against all known genotypes of HBV, and human papillomavirus (HPV) vaccines such as Gardasil-9 (approved 2014) and Cervarix (approved 2009), protecting against multiple HPV types associated with cervical cancer.^[3] Additionally, the hepatitis E virus (HEV) vaccine Hecolin (approved in China in 2011) demonstrates 100% efficacy against HEV genotype 1.^[3] In 2025, the VLP-based chikungunya vaccine VIMKUNYA was approved in the UK.^[4] Beyond human vaccines, VLPs are under development for veterinary use against pathogens like porcine circovirus type 2 and bluetongue virus, showing promise in preclinical models for livestock protection.^[3] Emerging uses extend to drug and gene delivery, cancer immunotherapy, and biomedical imaging, exploiting VLPs' nanoscale properties for targeted therapies and diagnostics.^[1]

Introduction

Definition and Characteristics

Virus-like particles (VLPs) are non-infectious, self-assembling nanostructures composed of viral structural proteins that mimic the morphology and antigenic properties of native viruses but lack any viral genetic material, such as DNA or RNA.^[1] These multiprotein assemblies form through spontaneous interactions of recombinant viral proteins, resulting in organized structures that replicate the conformation of authentic viral capsids without the capacity for replication.^[5] Key characteristics of VLPs include their capsid-like architecture, which can be hollow or solid, and their nanoscale dimensions, typically ranging from 20 to 200 nm in diameter.^[6] They exhibit repetitive surface epitopes that facilitate strong immune recognition by presenting antigens in a highly ordered, multivalent manner similar to viruses.^[1] Additionally, VLPs demonstrate high biocompatibility and structural stability, attributes that enable their use in biomedical applications without eliciting adverse immune responses to non-viral components.^[1] Unlike intact viruses, VLPs cannot replicate or cause infection due to the absence of genetic material, rendering them inherently safe for therapeutic and prophylactic purposes.^[7] VLPs are classified into basic types based on their protein composition: single-protein VLPs, such as those formed by the hepatitis B surface antigen (HBsAg), which self-assemble into spherical particles; and multipartite VLPs, which incorporate multiple viral proteins to form more complex structures mimicking multipartite viruses.^[8]^[1]

Historical Development

Virus-like particles were first observed via electron microscopy in 1966 in diseased Plantago lanceolata plants in Britain, marking early recognition of non-infectious viral mimics in natural plant infections.^[9] In plant pathology, further studies in the 1970s identified cryptic viruses, such as the beet cryptic virus in sugar beet (Beta vulgaris), which produce spherical particles resembling viruses but lacking infectivity.^[10] Intentional production of VLPs began in the 1980s with the advent of recombinant DNA technology, enabling the expression of viral structural proteins without genetic material. The first recombinant VLPs were visualized in 1982 using electron microscopy, demonstrating self-assembly of hepatitis B core antigen (HBcAg) into particulate structures in Escherichia coli.^[11] This breakthrough facilitated the development of the first VLP-based vaccine, Recombivax HB, a recombinant hepatitis B surface antigen (HBsAg) vaccine approved by the U.S. Food and Drug Administration (FDA) in 1986 for preventing hepatitis B virus infection.^[12] In parallel, plant VLP research gained traction, with early recombinant efforts in the late 1980s and 1990s leveraging systems like yeast for HBsAg and baculovirus for more complex assemblies. The 1990s saw significant milestones in VLP refinement and application, including the FDA approval of Engerix-B in 1989, another yeast-derived HBsAg VLP vaccine that improved immunogenicity over plasma-derived predecessors.^[13] Pioneering work on human papillomavirus (HPV) VLPs emerged in 1991, when Jian Zhou and Ian Frazer used recombinant DNA in insect cells to assemble HPV type 16 L1 protein into VLPs, demonstrating their potential as vaccine antigens.^[14] Structural elucidation advanced with the 2000 determination of the HPV16 L1 small VLP atomic model by Timothy S. Baker and colleagues, revealing pentameric capsomere organization and T=1 symmetry.^[15] Institutions like the University of Queensland (for HPV work) and early adopters of baculovirus expression systems drove these innovations, enabling scalable production. The landmark FDA approval of Gardasil in 2006, a quadrivalent HPV VLP vaccine targeting types 6, 11, 16, and 18, represented a major success, reducing cervical cancer risk through prophylactic immunization.^[16] By the 2000s, VLP research evolved from basic virology tools to engineered nanotechnology, with chimeric VLPs incorporating foreign epitopes for multivalent vaccines emerging post-2010. This shift emphasized modular designs, such as those fusing viral capsids with antigens from diverse pathogens, enhancing versatility in vaccine and delivery applications.^[16]

Structural Features

Composition and Components

Virus-like particles (VLPs) are constructed primarily from viral capsid proteins that self-assemble into stable, non-infectious structures resembling the protein shells of native viruses. These proteins, often expressed recombinantly in heterologous systems, oligomerize into symmetric units such as pentamers or hexamers, which further organize into icosahedral or spherical architectures. For instance, the major capsid protein L1 of human papillomavirus (HPV) self-assembles into pentameric capsomeres that arrange into a T=7 icosahedral lattice comprising 72 pentamers, forming empty particles approximately 55-60 nm in diameter.^[17] Similarly, the VP1 protein of parvoviruses, such as canine parvovirus, oligomerizes into 60 copies per capsid, with VP1 contributing unique N-terminal extensions that include a phospholipase A2 domain for membrane disruption during infection, though VLPs are typically produced using VP2 alone or in combination for structural integrity.^[18] VLPs incorporate both major and minor structural proteins to achieve their architecture, with major coat proteins forming the external shell and minor proteins providing internal scaffolding or functional support. Major proteins, like the hepatitis B surface antigen (HBsAg) in hepatitis B virus (HBV) VLPs, self-assemble into 22-nm spherical particles composed solely of this glycoprotein, which dimerizes and further aggregates without requiring additional viral components.^[19] In contrast, minor proteins such as VP2 and VP3 in parvoviruses serve scaffold roles; VP2 includes an N-terminal nuclear localization signal for capsid trafficking, while VP3, a proteolytic product of VP2 lacking this extension, constitutes the bulk of the exposed surface in mature capsids, with VP1 typically comprising 5-10 copies and VP2/VP3 the remaining ~50-55 copies per 60-subunit capsid in natural virions; similar proportions are used in VLPs.^[18]^[20] For norovirus VLPs, the single major protein VP1 features a protruding (P) domain that extends from the shell (S) domain, enabling trimerization and T=3 icosahedral assembly into 38-nm particles.^[21] Beyond viral proteins, VLPs can integrate non-viral elements to enhance functionality while remaining non-infectious. Enveloped VLPs, such as those derived from hepatitis C virus (HCV), incorporate host-derived lipids into a bilayer surrounding core and glycoprotein components (E1/E2), mimicking the 40-60 nm enveloped virion structure.^[5] Non-infectious nucleic acids, often host cell-derived RNA or packaged plasmids, may be enclosed within the capsid; for example, simian virus 40 (SV40) VLPs can encapsulate DNA up to 17.7 kb for gene delivery applications without replication capacity.^[5] Hybrid VLPs further incorporate heterologous proteins through genetic fusion or co-expression, such as HBV core particles displaying HIV epitopes or HPV L1-L2 chimeras that include minor capsid protein L2 for improved stability and immunogenicity.^[5] These additions allow customization while preserving the core self-assembling properties of the viral proteins.

Morphology and Size

Virus-like particles (VLPs) exhibit a variety of morphologies that mimic the structural forms of their parental viruses, including spherical, rod-shaped, and filamentous configurations. Spherical VLPs, often adopting icosahedral symmetry, are among the most common and include examples such as hepatitis B core (HBc) VLPs, which form icosahedral particles with T=3 or T=4 symmetry.^[22] Human papillomavirus (HPV) VLPs also display spherical icosahedral morphology, self-assembling from major capsid protein L1 into T=7 structures.^[1] In contrast, rod-shaped VLPs are exemplified by those derived from tobacco mosaic virus (TMV), which assemble into elongated helical rods.^[23] Filamentous VLPs, such as certain influenza-derived particles, can elongate into thread-like forms depending on the expressed viral components.^[1] The size of VLPs varies significantly based on the originating virus and structural design, typically ranging from 20 nm to over 200 nm in diameter. Small VLPs, such as those from parvoviruses, measure approximately 20-30 nm in diameter and exhibit simple T=1 icosahedral symmetry composed of 60 capsid protein subunits.^[24] Medium-sized VLPs, like HPV particles, have diameters of 40-60 nm and incorporate around 360 copies of the L1 protein organized into 72 pentameric capsomers.^[1] Larger VLPs, including influenza-based ones, can reach 100-200 nm, reflecting their more complex envelope-like architecture with hemagglutinin spikes.^[6] Overall, VLP dimensions fall within the nanoscale range of native viruses (22-150 nm), enabling efficient cellular interactions while lacking genetic material.^[6] Morphology and size are influenced by factors such as icosahedral triangulation numbers (T=1 to T=7), which dictate subunit arrangement and particle curvature, as seen in the progression from compact parvovirus (T=1) to larger HPV (T=7) forms.^[1] Multimerization of capsid proteins, such as the 180-360 subunits in HBV and HPV VLPs, further stabilizes these shapes.^[22] Environmental conditions, including pH, can modulate assembly and stability; for instance, acidic pH promotes disassembly in some icosahedral VLPs, while neutral conditions favor intact spherical forms.^[1] Structural confirmation of VLP morphology and size relies on advanced imaging techniques. Cryo-electron microscopy (cryo-EM) provides high-resolution three-dimensional reconstructions, as demonstrated in analyses of influenza VLPs revealing diameters up to 221 nm and surface spike details.^[25] Atomic force microscopy (AFM) complements this by offering surface topography at the single-particle level, useful for assessing size distributions and conformational variability in rod-shaped TMV VLPs.^[26] These methods ensure precise characterization without altering particle integrity.^[1]

Production Methods

Expression Systems

Virus-like particles (VLPs) are produced using various expression systems that leverage host cells to express viral structural proteins, enabling self-assembly into non-infectious particles mimicking viral morphology.^[27] Prokaryotic systems, particularly Escherichia coli, are commonly employed for simple bacterial VLPs due to their cost-effectiveness, rapid growth, and high yields.^[28] For instance, E. coli has been used to produce Qβ phage VLPs, where the coat protein self-assembles into particles after expression via recombinant vectors.^[29] These systems achieve yields up to 100 mg/L for certain VLPs, such as those from bacteriophage-derived capsids, making them suitable for scalable production of non-glycosylated particles.^[30] However, prokaryotic hosts lack the machinery for eukaryotic post-translational modifications like glycosylation, limiting their use to simpler VLPs and requiring additional purification to remove endotoxins.^[27] Eukaryotic expression systems offer improved capabilities for post-translational modifications, supporting more complex VLPs. Yeast systems, including Saccharomyces cerevisiae and Pichia pastoris, are utilized for hepatitis B virus (HBV) VLPs, where the surface antigen (HBsAg) is expressed and assembles in vivo, providing basic glycosylation and high-density cell growth.^[28] These platforms yield 15-24 mg/L for HBV VLPs and are cost-effective without endotoxin risks, as seen in commercial products like Recombivax HB.^[27] Baculovirus-insect cell systems, such as Sf9 cells, excel in producing intricate VLPs like those from human papillomavirus (HPV), enabling accurate protein folding and modifications through transient infection.^[28] Yields in insect cells typically range from 10-50 mg/L for HPV VLPs, supporting high immunogenicity in vaccines like Gardasil.^[31] Mammalian cell systems, notably human embryonic kidney (HEK293) cells, provide human-like glycosylation essential for therapeutic VLPs requiring precise post-translational processing to enhance stability and immunogenicity.^[28] These systems are used for VLPs such as those from influenza or SARS-CoV-2, with yields around 1-5 mg/L, though they incur higher costs and lower scalability compared to other hosts.^[27] Plant-based systems, exemplified by Nicotiana benthamiana, facilitate transient expression via Agrobacterium-mediated infiltration, yielding VLPs like those from norovirus at up to 0.5-1 g/kg fresh leaf weight.^[27] This approach offers low-cost, scalable production without animal-derived pathogens, though plant-specific glycosylation patterns may necessitate engineering for optimal performance.^[28] Among these, insect cell systems are preferred for many commercial VLPs due to their balance of high yields (10-50 mg/L), accurate folding, and eukaryotic modifications, as evidenced by dominant use in HPV and influenza vaccines.^[28] Prokaryotic systems prioritize yield for basic VLPs but falter on complexity, while mammalian and plant platforms excel in mimicry and affordability, respectively, guiding selection based on VLP requirements.^[27] Recent advances as of 2025 include the optimization of Chinese hamster ovary (CHO) cells for stable, high-yield production of foot-and-mouth disease virus VLPs and directed evolution of engineered VLPs to enhance production efficiency and cargo loading.^[32]^[33]

Assembly Processes

Virus-like particles (VLPs) primarily form through self-assembly, a spontaneous process where capsid proteins oligomerize into organized, virus-mimicking structures without requiring viral genetic material. This assembly is driven by non-covalent interactions such as hydrophobic forces, which stabilize coiled-coil structures in alphavirus cores like those of Sindbis virus, and electrostatic interactions that maintain VLP integrity in plant viruses such as pepper vein banding potyvirus.^[34] Disulfide bonds further reinforce these structures, particularly in icosahedral VLPs like human papillomavirus (HPV), where they link L1 protein pentamers into a T=7 capsid lattice.^[35] For helical VLPs, such as those derived from tobacco mosaic virus (TMV), assembly is often pH-dependent, with coat proteins aggregating into rod-like forms under neutral conditions.^[34] Assembly can occur either in vivo, within host cells during protein expression, or in vitro, using purified components. In vivo assembly typically involves co-expression of multiple structural genes in cellular environments, such as baculovirus systems co-infecting insect cells to produce multi-subunit VLPs like those for HPV, where L1 proteins spontaneously form particles in the cytoplasm or nucleus.^[36] In contrast, in vitro methods rely on mixing purified proteins, as seen in TMV rod formation by incubating coat proteins at neutral pH, or in cell-free systems for HPV16, where L1 pentamers nucleate into VLPs through concentration-dependent dimerization.^[37]^[38] Directed assembly enhances control over VLP formation by incorporating scaffolds or cross-linkers to dictate stoichiometry and morphology. Nucleic acid scaffolds, for instance, guide TMV coat proteins to assemble around specific RNA sequences like the origin-of-assembly motif, mimicking native virion packaging.^[34] Chemical cross-linkers, such as organoplatinum(II) complexes, stabilize cowpea chlorotic mottle virus (CCMV) VLPs during in vitro reconstruction, while chimeric designs enable VLPs to form around non-native cores, as in HPV variants incorporating foreign epitopes for targeted oligomerization.^[37]^[34] Several factors influence assembly efficiency, including environmental conditions that prevent misfolding or aggregation. Optimal temperatures range from 20°C to 37°C, with lower ranges (e.g., 4°C) used for sensitive VLPs like parvovirus B19 to minimize off-target interactions, while physiological temperatures promote kinetics in systems like Rous sarcoma virus.^[37] Ionic strength modulates protein charge and stability, as higher salt concentrations (e.g., 0.5 M NaCl) facilitate hepatitis E virus VLP formation by screening repulsive forces.^[37] Chaperones, such as L-arginine or tRNA mimics, aid folding in bromoviruses and HIV-1 VLPs, reducing aggregation and improving yields.^[34]^[37]

Surface Engineering

Targeting Ligand Attachment

One primary method for attaching targeting ligands to virus-like particles (VLPs) is genetic fusion, where ligand-encoding sequences are inserted into the genes of capsid proteins using recombinant DNA techniques. This approach integrates the ligands directly into the VLP structure during self-assembly, ensuring uniform display on the particle surface without compromising morphological integrity. For instance, the RGD peptide, known for binding αvβ3 integrin receptors on angiogenic endothelial cells, has been genetically fused to adeno-associated virus (AAV) capsid proteins, enabling targeted gene delivery while preserving VLP assembly efficiency.^[39] Similar fusions in AAV VLPs have demonstrated enhanced tropism for specific cell types, such as those overexpressing integrins, by modifying variable regions of the capsid without disrupting overall particle formation.^[40] Chemical conjugation represents another key strategy for post-assembly ligand attachment, allowing flexibility in linking diverse targeting moieties to preformed VLPs via covalent bonds to surface-exposed amino acids. N-hydroxysuccinimide (NHS) esters react selectively with primary amines on lysine residues, while maleimides form stable thioether bonds with cysteine thiols, both enabling precise functionalization for directed delivery. These chemistries have been applied to hepatitis B virus (HBV) VLPs, where antibodies or peptides are conjugated to enhance specificity toward tumor cells. For example, a tumor-homing peptide (tLyP-1) was covalently linked to Flock House virus VLPs using NHS-mediated crosslinking, resulting in approximately 90 ligands per particle and improved uptake in neuropilin-expressing cancer cells.^[41] Such methods maintain VLP stability and symmetry, with conjugation yields optimized by controlling reaction stoichiometry to avoid over-modification.^[42] For more controlled and orthogonal attachment, site-specific strategies like the SpyTag/SpyCatcher system minimize disruption to VLP architecture by enabling ligand coupling at predefined sites. SpyTag, a short peptide tag, is genetically incorporated into capsid proteins, where it spontaneously forms an irreversible isopeptide bond with the SpyCatcher protein fused to the targeting ligand upon simple mixing at physiological conditions. This bioorthogonal reaction has been utilized in Acinetobacter phage AP205-derived VLPs to display cell-targeting peptides, preserving particle symmetry and achieving high-density ligand presentation without chemical reagents.^[43] The system's modularity supports rapid prototyping of targeted VLPs, as demonstrated in enhanced uptake studies with various receptor-binding partners.^[44] A notable application involves HER2-targeted VLPs for cancer therapy, where affibodies specific to the HER2 receptor are genetically inserted into HBV core particles, facilitating selective binding and internalization in HER2-overexpressing tumor cells.^[45] This strategy leverages the 180-240 monomers per particle for multivalent display, balancing avidity and steric constraints for optimal delivery precision.

Functionalization Strategies

Functionalization strategies for virus-like particles (VLPs) enable the integration of diverse functional groups to enhance their performance in biomedical and nanotechnological contexts, distinct from targeting-specific modifications. These approaches leverage the structural versatility of VLPs to incorporate cargos, amplify signals, or impart new properties like stealth or fusion capabilities. By modifying internal cavities or external surfaces, VLPs can serve as versatile platforms for drug delivery, imaging, and material assembly. As of 2025, recent advances include directed evolution of engineered VLPs for improved stability and targeting efficiency in gene delivery.^[33] Encapsulation methods involve loading therapeutic agents or enzymes into VLP interiors, often exploiting reversible disassembly and reassembly under controlled conditions such as pH shifts. For bacteriophage MS2 VLPs, lowering the pH to around 3.5 disassembles the capsid into dimers, allowing cargo infusion, followed by neutralization to pH 7.4 for reassembly and encapsulation.^[46] This technique has been used to package chemotherapeutic drugs like doxorubicin within MS2 VLPs, enabling targeted delivery to cancer cells with reduced off-target effects compared to free drug. Enzymes can similarly be encapsulated, protecting them from degradation and facilitating controlled release in response to environmental triggers. Multivalent display strategies engineer the repetitive surface architecture of VLPs to present multiple copies of functional moieties, amplifying biological signaling or interactions. Genetic or chemical modifications allow attachment of epitopes or nanomaterials to coat proteins, exploiting the icosahedral symmetry for high-density presentation. For instance, cowpea mosaic virus (CPMV) VLPs decorated with gold nanoparticles via bioconjugation exhibit enhanced plasmonic properties and multivalent binding, improving sensitivity in biosensing applications through amplified electromagnetic signals.^[47] Bioconjugation tools, particularly click chemistry variants, provide efficient, site-specific attachment of non-targeting groups to VLP surfaces. Copper-catalyzed azide-alkyne cycloaddition (CuAAC) enables covalent linking of fluorophores to azido-modified VLPs, facilitating high-resolution imaging without compromising particle integrity. Strain-promoted azide-alkyne cycloaddition (SPAAC) offers a copper-free alternative, used to conjugate polyethylene glycol (PEG) chains to VLPs for improved circulation half-life and stealth against immune clearance.^[42] These reactions achieve near-quantitative yields under mild conditions, preserving VLP stability. Hybrid approaches incorporate lipids into non-enveloped VLPs to create lipo-VLPs that mimic enveloped virus structures, promoting membrane fusion-like behaviors for enhanced cellular uptake. Lipids are integrated during assembly or post-production via detergent-mediated insertion, forming a bilayer around the VLP core. Such lipo-VLPs, derived from platforms like hepatitis B core antigen, exhibit fusion with endosomal membranes, enabling cytosolic release of encapsulated payloads and bypassing lysosomal degradation.^[48]

Biomedical Applications

Vaccine Platforms

Virus-like particles (VLPs) serve as effective vaccine platforms by mimicking the structural organization of viruses, presenting repetitive antigenic epitopes on their surface that closely resemble those of native pathogens. This repetitive display triggers robust B-cell activation and antibody production, often without the need for adjuvants, while also eliciting T-cell helper responses to enhance immunogenicity. Unlike live-attenuated or inactivated vaccines, VLPs pose no risk of infection or replication since they lack viral genetic material.^[27]^[16] Several VLP-based vaccines have received regulatory approval for human use, demonstrating their clinical efficacy in preventing viral infections. The human papillomavirus (HPV) vaccine Gardasil 9, approved by the U.S. Food and Drug Administration in December 2014, utilizes VLPs derived from the L1 capsid protein of nine HPV strains (types 6, 11, 16, 18, 31, 33, 45, 52, and 58) to protect against cervical, anal, and other HPV-related cancers and genital warts.^[49] For hepatitis B virus (HBV), Recombivax HB employs recombinant hepatitis B surface antigen (HBsAg) that self-assembles into VLPs, providing protection against HBV infection across all known subtypes; it was approved by the FDA in 1986.^[50] Similarly, the hepatitis E virus (HEV) vaccine Hecolin, based on truncated HEV capsid protein VLPs, was approved in China in 2011 for individuals aged 18 and older at high risk of infection.^[51] Ongoing development pipelines highlight VLPs' versatility for emerging pathogens, including norovirus and influenza. Norovirus VLP vaccines, such as HIL-214 targeting the VP1 capsid protein, advanced to Phase IIb trials in the 2020s but failed to meet primary efficacy endpoints in 2024 (showing 5% efficacy against GII.4 strains in infants); further development is under evaluation as of 2025, with promise in eliciting protective antibodies in earlier studies.^[52]^[53] Chimeric VLPs for universal influenza vaccines incorporate conserved epitopes from hemagglutinin (HA) and neuraminidase (NA) across multiple strains, inducing broad cross-protection against seasonal and pandemic variants in preclinical and early clinical studies.^[54] As of 2025, VLP-based vaccines continue in clinical trials for pathogens like SARS-CoV-2 and universal influenza, with no additional approvals reported.^[54] Compared to traditional subunit or inactivated vaccines, VLP platforms offer superior immunogenicity, often generating 10- to 100-fold higher antibody titers and promoting mucosal immunity for enhanced protection at entry sites. Their particulate nature and stability further contribute to efficient immune recognition and long-lasting responses without the safety concerns of live vaccines.^[55]^[56]

Therapeutic Delivery Systems

Virus-like particles (VLPs) have been engineered as versatile nanocarriers for therapeutic delivery, enabling the encapsulation and targeted transport of drugs and nucleic acids to diseased tissues without the risks associated with live viruses. These non-infectious structures mimic viral architecture to facilitate cellular uptake and controlled payload release, particularly in cancer and viral disease treatments. By leveraging their nanoscale size (typically 20-200 nm), VLPs evade rapid renal clearance while promoting endocytosis in target cells.^[57] Drug loading into VLPs often involves internal packaging of therapeutics such as small interfering RNA (siRNA) for gene silencing. For instance, cowpea chlorotic mottle virus (CCMV)-derived VLPs have been used to encapsulate siRNA targeting green fluorescent protein (GFP), demonstrating efficient delivery and silencing in mammalian cells without toxicity. Targeted release is achieved through pH-sensitive disassembly, where VLPs remain stable at physiological pH (7.4) but disassemble in acidic endosomal environments (pH ~5.5), liberating the cargo. Hepatitis B core antigen (HBc) VLPs exemplify this, releasing up to 70% of encapsulated doxorubicin over 48 hours at endosomal pH 5.0, with slower release at physiological pH 7.4, enhancing chemotherapeutic efficacy while minimizing off-target effects in tumor microenvironments (pH 6.5-6.8).^[58]^[59] In gene therapy, VLPs serve as safe vectors by pseudotyping with viral envelopes like vesicular stomatitis virus glycoprotein (VSV-G), which confers broad tropism for cell transduction without genomic integration or insertional mutagenesis risks. Engineered VLPs packaging CRISPR-Cas9 ribonucleoproteins, pseudotyped with VSV-G, have achieved efficient editing in retinal pigment epithelium cells, supporting applications in inherited retinal diseases. These systems enable transient expression of therapeutic proteins, such as prime editors, with high fidelity and low immunogenicity.^[60]^[61] Clinical translation of VLP-based therapeutics includes phase I/II trials for cancer immunotherapy, such as the Qβ(G10)-Melan-A VLP vaccine, which delivered melanoma antigens to elicit T-cell responses in stage II/IV patients, showing safety and immunogenicity in the 2010s. For HIV, the therapeutic p24-VLP derived from Gag capsid progressed to phase I/II studies, demonstrating antigen-specific immune activation in infected individuals without viral replication. Pharmacokinetics of VLPs support their utility, with circulation half-lives exceeding 24 hours—such as ~44 hours for Physalis mosaic virus (PhMV) VLPs—due to their size and PEGylation, allowing sustained systemic exposure before tissue accumulation. Surface targeting ligands can further enhance specificity, as briefly integrated from prior engineering strategies.^[62]^[63]^[59]

Diagnostic and Imaging Tools

Virus-like particles (VLPs) have emerged as versatile platforms for diagnostic and imaging applications, leveraging their nanoscale structure and multivalent surfaces to enhance detection sensitivity and specificity in biomarker identification and in vivo visualization. By conjugating imaging agents to VLPs, researchers can achieve targeted labeling that improves signal detection in complex biological environments, such as tumors or infected tissues.^[64] A key aspect of VLP-based imaging involves the attachment of fluorophores, which enable high-resolution optical tracking of cellular interactions and viral mimicry processes. For instance, fluorophore-conjugated VLPs, such as those derived from bacteriophage Qβ, have been used to visualize receptor-ligand dynamics on cell surfaces with minimal background interference. Radionuclides like ⁶⁴Cu, chelated via DOTA and incorporated into plant virus-derived VLPs such as MS2 bacteriophage nanoparticles, facilitate positron emission tomography (PET) for non-invasive tumor imaging in mouse models, allowing quantification of VLP accumulation in xenografts. Additionally, quantum dots encapsulated within or conjugated to VLPs, including canine parvovirus-like particles, support multicolor tracking, enabling simultaneous monitoring of multiple VLP subpopulations during endocytosis or tissue penetration in live cells.^[65]^[64]^[66] In diagnostic assays, VLPs displaying specific antigens provide a robust scaffold for detecting antibodies through ELISA-like formats, offering advantages over soluble antigens due to their structural integrity and repetitive epitopes. For example, SARS-CoV-2 spike protein-displaying VLPs have been employed in enzyme-linked immunosorbent assays (ELISAs) to quantify IgG antibodies in human serum, demonstrating high specificity and sensitivity comparable to commercial kits during the 2020 pandemic response. These assays exploit the multivalent antigen presentation on VLPs to amplify binding signals, facilitating rapid serological screening.^[67] For in vivo applications, iron oxide-loaded VLPs enhance magnetic resonance imaging (MRI) contrast by serving as T2-weighted agents that shorten relaxation times in targeted tissues. Bacteriophage M13 VLPs displaying superparamagnetic iron oxide nanoparticles have shown prolonged circulation and targeting in rodent models, providing clear T2 hypointensity for organ-specific imaging. Real-time tumor homing can be visualized using near-infrared fluorescently labeled VLPs, such as Physalis mottle virus-like nanoparticles conjugated with Alexa Fluor 647, which demonstrate enhanced penetration and retention in prostate tumor xenografts via intravital microscopy in mice, revealing dynamic accumulation over 24 hours.^[68]^[69] The multivalency of VLPs significantly boosts signal-to-noise ratios in imaging by concentrating multiple labels per particle, thereby amplifying detectable signals relative to background noise compared to monovalent probes. This property has been shown to improve diagnostic imaging contrast in preclinical studies, with VLPs providing up to 10-fold higher signal intensity in fluorescence-based tumor detection. Functionalization strategies, including covalent bioconjugation, allow precise attachment of these imaging labels to VLP surfaces without compromising structural stability.^[70]^[64]

Materials and Nanotechnology Uses

Bio-Inspired Material Design

Virus-like particles (VLPs) serve as versatile bio-inspired templates in material design, leveraging their self-assembling proteinaceous structures to guide the synthesis of advanced nanomaterials that mimic viral architectures. These non-infectious scaffolds enable precise control over nanoscale organization, facilitating the creation of hierarchical materials with enhanced mechanical and optical properties. By exploiting the symmetric, monodisperse morphology of VLPs—such as icosahedral or rod-like forms—researchers can direct the deposition of inorganic components, resulting in composites that outperform traditional synthetic nanoparticles in uniformity and biocompatibility.^[71] In templating applications, VLPs act as scaffolds for mineralizing metals and oxides, promoting uniform nucleation and growth on their surfaces. For instance, cowpea chlorotic mottle virus (CCMV) particles, a type of plant VLP, have been electrostatically assembled with avidin proteins to form heterogeneous crystals incorporating organic dyes, yielding structures with fluorescent properties.^[72] Similarly, cowpea mosaic virus (CPMV) VLPs have been used to template silica nanoparticles through surface modification, enabling the fabrication of coated nanostructures with controlled shell thicknesses for potential use in sensing and catalysis.^[73] These approaches capitalize on the VLPs' exposed amino acid residues to anchor precursors, ensuring high-fidelity replication of viral geometries in the resulting inorganic-organic hybrids.^[74]^[73] Hierarchical assembly techniques further expand VLP utility, employing layer-by-layer (LbL) deposition to build complex 3D nanostructures. Multi-valent protein linkers mediate the ordered stacking of VLPs, such as Salmonella typhimurium P22 capsids, into multilayered arrays with tunable interlayer spacing. This method has been applied to create scaffolds for tissue engineering, where virus-based 2D films evolve into 3D porous matrices that support cell adhesion and proliferation without eliciting immune responses. Representative examples include tobacco mosaic virus (TMV) rod-shaped VLPs serving as templates for metallic nanowires in electronic devices, where peptide-directed mineralization yields conductive cobalt or platinum nanowires with diameters matching the VLP's 18 nm width. In the 2020s, TMV VLPs have also been integrated into hydrogels via covalent click chemistry, forming swellable networks for implantable scaffolds with enhanced structural integrity.^[75]^[76]^[77]^[78] VLPs offer sustainable alternatives to synthetic nanoparticles, being fully biodegradable and derived from renewable biological sources, which reduces environmental impact in material production. Their inherent architecture provides tunable porosity, typically ranging from 1-10 nm, allowing for customizable diffusion properties in the engineered materials. This biodegradability, combined with precise assembly, positions VLP-templated designs as eco-friendly options for next-generation nanocomposites in electronics and structural applications.^[79]^[80]

Lipoparticle and Sensor Technologies

Lipoparticles represent hybrid systems where virus-like particles (VLPs) are fused or associated with liposomes, incorporating lipid bilayers that mimic viral envelopes to facilitate enhanced membrane penetration and cellular delivery. These structures, typically 100-200 nm in diameter, display membrane proteins in their native conformation at high densities (50-200 pmol/mg), enabling quantitative studies of protein-lipid interactions and fusion mechanisms without infectious risk. For instance, lipoparticles derived from retroviral-like particles combined with cationic liposomes such as DOTAP and DOPE have been engineered for gene delivery, promoting endosomal escape and membrane fusion through lipid mixing. In fusion studies, influenza VLPs incorporating hemagglutinin (HA) glycoproteins within lipid bilayers have been used to model pH-triggered membrane fusion, revealing how HA conformational changes drive hemifusion intermediates and lipid exchange with target membranes.^[81]^[82]^[83] Biosensor integration leverages VLPs immobilized on transducer surfaces, such as electrodes or quartz crystals, to create sensitive platforms for pathogen detection by exploiting VLP multivalency and antigen mimicry. In electrochemical setups, VLPs functionalized with gold nanoparticles serve as bioreceptors on electrodes, enabling label-free detection through changes in redox currents or impedance upon analyte binding. A notable example involves HIV-1 VLPs assembled on thiolated DNA-modified gold electrodes, where binding of viral particles alters electron transfer, enabling quantification via differential pulse voltammetry. For reovirus-inspired lipo-VLPs, hybrid lipid-VLP formulations have been explored as vaccine adjuvants, enhancing immunogenicity by promoting membrane fusion-like uptake in antigen-presenting cells, though primarily demonstrated in non-enveloped VLP-lipid hybrids like norovirus VLPs with lipid nanoparticles that boost antibody responses without traditional adjuvants.^[84]^[85] Quartz crystal microbalance (QCM) sensors utilizing norovirus VLPs illustrate high sensitivity in detecting viral binding to host receptors, such as histo-blood group antigens in lipid bilayers. These sensors monitor frequency shifts and dissipation upon VLP adsorption, with proximity ligation assays enabling subpicogram (10^{-13} g) detection limits for norovirus-like particles, corresponding to subattomolar concentrations suitable for low-viral-load samples. Advancements in the 2020s include nanoplasmonic VLPs with gold cores arranged in periodic arrays, amplifying localized surface plasmon resonance (LSPR) signals for point-of-care diagnostics; for example, SARS-CoV-2 spike-functionalized plasmonic VLPs achieve single-particle sensitivity (1 VLP/μL) through antibody-mediated binding shifts in refractive index. These hybrid systems, distinct from pure bio-inspired templating, prioritize detection device integration for rapid, on-site pathogen identification.^[86]^[87]^[88]

Advantages and Future Directions

Key Benefits

Virus-like particles (VLPs) exhibit a superior safety profile compared to live viral vectors due to their non-replicative nature, which eliminates the risk of uncontrolled replication or reversion to virulence. This inherent safety has been demonstrated in multiple FDA-approved VLP-based vaccines, including those for hepatitis B virus (Engerix-B) and human papillomavirus (Gardasil), which have been safely administered to millions without evidence of integration into host genomes or pathogenic effects. Recent approvals, such as the chikungunya vaccine Vimkunya in 2025, further underscore VLPs' low immunogenicity risks relative to live-attenuated viruses, as they lack viral genetic material while mimicking native viral structures.^[89] The particulate architecture of VLPs significantly enhances immunogenicity over soluble antigens, with their repetitive, high-density antigen display promoting efficient uptake by antigen-presenting cells and leading to robust humoral and cellular immune responses. This versatility allows straightforward engineering for multifunctionality, such as incorporating adjuvants or targeting ligands, without compromising structural integrity, as evidenced in platforms like bacteriophage Qβ VLPs that elicit potent antibody production. VLPs' ability to stimulate both innate and adaptive immunity pathways positions them as highly adaptable for diverse applications. VLPs offer advantages in scalability and cost-effectiveness through established expression systems, achieving high yields up to 1-2 g/kg fresh leaf weight in plant-based production, which leverages transient agroinfiltration for rapid, low-cost manufacturing.^[90] Their proteinaceous composition ensures biodegradability, reducing environmental persistence compared to synthetic nanoparticles. VLPs generally exhibit enhanced serum stability with longer circulation half-lives than free proteins due to reduced proteolysis and evasion of rapid clearance, while their uniform nanoscale size (typically 20-200 nm) ensures reproducible pharmacokinetics and biodistribution.^[1]

Challenges and Limitations

One major hurdle in virus-like particle (VLP) development is the low production yields, particularly for complex VLPs in mammalian expression systems, where outputs often range from 0.018 to 10 mg/L due to inefficient protein folding, assembly, and scale-up limitations.^[91] Purification further exacerbates these issues, as VLP heterogeneity in size, structure, and stability—stemming from incomplete assembly or host cell contaminants—necessitates multi-step processes like chromatography and ultracentrifugation, which reduce overall recovery and increase costs.^[92] Immunologically, VLPs can elicit unwanted anti-VLP immune responses during repeated dosing, leading to carrier-induced epitopic suppression that diminishes the targeted antigen-specific efficacy by interfering with antigen presentation and uptake.^[93] Batch-to-batch variability, often caused by inconsistent encapsulation of host-cell proteins and nucleic acids during assembly, further compromises immunological consistency and vaccine potency across productions.^[94] Regulatory and ethical challenges include extended approval timelines for VLP-based therapeutics, typically spanning 10 to 15 years from preclinical development to licensure, driven by rigorous safety assessments for biologics.^[95] In gene delivery applications, concerns persist over potential off-target editing effects, despite VLPs offering transient delivery that reduces risks compared to integrating viral vectors.^[60] Emerging solutions aim to address these limitations through AI-optimized VLP designs, leveraging post-2020 computational models for epitope prediction and structural engineering to enhance yield and uniformity.^[96] CRISPR-edited expression systems in host cells promise greater VLP homogeneity by precisely modifying production pathways to minimize variability. Additionally, non-vaccine VLP applications are advancing, with ongoing Phase II clinical trials for cancer immunotherapies using VLP platforms to deliver tumor antigens, including those targeting melanoma and breast cancer.^[97] Recent research also explores VLPs for mRNA delivery and rapid pandemic vaccine platforms as of 2025.^[60]

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