Role of exosomes in viral infections: a narrative review

Roberta Della Marca; Rosa Giugliano; Carla Zannella; Marina Acunzo; Preetu Parimal; Avinash Mali; Annalisa Chianese; Valentina Iovane; Massimiliano Galdiero; Anna De Filippis

doi:10.1016/j.virusres.2025.199644

. 2025 Oct 17;361:199644. doi: 10.1016/j.virusres.2025.199644

Role of exosomes in viral infections: a narrative review

Roberta Della Marca ^a,¹, Rosa Giugliano ^a,^b,¹, Carla Zannella ^a, Marina Acunzo ^a, Preetu Parimal ^a, Avinash Mali ^c, Annalisa Chianese ^a, Valentina Iovane ^d, Massimiliano Galdiero ^a,^e, Anna De Filippis ^a,^⁎

PMCID: PMC12593684 PMID: 41110646

Highlights

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Exosomes act as both antiviral defenders and viral facilitators.
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Viral exosomes enhance replication, spread, and immune evasion.
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Physiological exosomes boost immune surveillance and host defense.
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The dual role of exosomes underscores their context-dependent functions.
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Exosomes represent promising biomarkers and therapeutic tools.

Keywords: Exosomes, Viral infection, Viral pathogenesis, Virus-host interaction, Exosomes roles, Human and animal pathogens

Abstract

Exosomes are a type of extracellular vesicles (EVs) released by cells under normal and pathological conditions. These lipid-enclosed vesicles play a key role in intracellular communication by delivering various molecules, such as proteins, nucleic acids, and lipids, thereby influencing the activity of recipient cells. In recent years, exosomes have attracted considerable attention for their involvement in viral infections and immune system evasion. Many viruses hijack the exosome biogenesis machinery to facilitate their replication, spread infection, and evade immune defenses. Therefore, gaining insights into how exosomes modulate the immune system or contribute to viral infectivity is crucial. This review explores how viral exosomes interact with host mammalian cells, highlighting their unique ability to transfer genetic material and proteins to recipient cells independent of virus-receptor interaction. Additionally, we examine the role of viral exosomes in intercellular communication, particularly how they may both promote viral infectivity and transmission, as well as participate in antiviral defense and immune regulation. Unlike previous reviews, our study integrates findings across both human and animal viral infections, critically discusses methodological standardization in exosome research, and introduces emerging therapeutic approaches such as engineered exosomes and exosome mimetics.

Graphical abstract

1. Introduction

Extracellular vesicles (EVs) are nano-sized, lipid bilayer-enclosed particles released by a wide range of cell types into the extracellular milieu. They originate either from the plasma membrane or from intracellular endosomal compartments (Petrovčíková et al., 2018). EVs play a pivotal role in intercellular communication by serving as carriers of diverse biomolecules, such as proteins, lipids, and nucleic acids, which they deliver to recipient cells (Yanez-Mo et al., 2015; Maas et al., 2017). Depending on their biogenesis, size, and structural characteristics, EVs are generally classified into three major subtypes: i) exosomes: small vesicles (30-150 nm in diameter) that originate from the inward budding of endosomal membranes, leading to the formation of multivesicular bodies (MVBs), also called multivesicular endosomes (MVEs), which subsequently fuse with the plasma membrane to release exosomes into the extracellular space; ii) microvesicles (MVs): vesicles ranging from 100 to 1000 nm in diameter, formed by the outward budding and fission of the plasma membrane; iii) apoptotic bodies: large vesicles (1000-5000 nm) released as membrane blebs from cells undergoing programmed cell death (apoptosis) (Yanez-Mo et al., 2015; Schwab et al., 2015).

1.1. Advantages and methodological challenges in exosomes research

Among the various subtypes of EVs, exosomes are the most extensively studied and have garnered significant attention in recent years across various fields, including gene and drug delivery, as well as in the development of prognostic and diagnostic biomarkers. This interest stems from their involvement in numerous physiological processes and pathological conditions (Zhanget al., 2018; Sluijter et al., 2018). Despite significant advancements, exosome research is hindered by several methodological challenges, particularly in the areas of isolation, characterization, and reproducibility. These limitations largely arise from the intrinsic heterogeneity of exosomes, difficulties in effectively separating them from other EVs and co-isolating contaminants, and the absence of standardized protocols. A summary of currently employed exosome isolation techniques is provided in Table 1 (Habib et al., 2023).

Table 1.

Different methodologies for exosome isolation, associated with their main advantages and limitations.

Methodology	Separation principle	Advantages	Disadvantages	Yield	Scalability	References
Ultra-centrifugation	Size, density, and sedimentation properties	Cost-effective High purity	Low recovery, requires expensive equipment, long centrifugation step, time-consuming, large sample demand	Medium	Moderate	(Helwa et al., 2017)
Immuno-affinity	Affinity	High purity	High cost, limited sample throughput, may miss exosomes lacking the target marker	Low	Low	(Sharma et al., 2018)
Size-exclusion chromatography	Size	Easy, low cost, high purity	Low specificity, possible protein contamination. Not suitable for big volumes, requires specific equipment	Medium	High	(Boing et al., 2014)
Precipitation method	Polymer precipitation	Easy, fast method	Low purity (co-precipitates proteins/impurities), variable reproducibility	High	High	(Soares Martins et al., 2018)
Microfluidics method	Size, density, and chemical properties	High purity, fast, and sample method	Complex device design, expensive, still under development for large-scale, time-consuming procedures	Low-Medium	Low-Moderate	(Shirejini and Inci, 2018)

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Isolation of exosomes from virus-infected cells poses additional complexities. For instance, cultures infected with viruses that induce significant cytopathic effects can release a high amount of cellular debris and apoptotic bodies that contaminate EV preparations (Xu et al., 2023). To address this, differential centrifugation combined with density gradient ultracentrifugation is often employed to separate exosomes from larger vesicles and cellular fragments based on size and buoyant density (Kowal et al., 2016; Chaudhari et al., 2022).

However, the overlap in size and density between exosomes and enveloped virions, such as coronaviruses, complicates their separation, as both possess lipid membranes and similar biophysical properties (Zhang et al., 2021). Immunoaffinity-based isolation techniques targeting specific exosomal surface markers (e.g., CD9, CD63, CD81) have been shown to effectively separate exosomes from virions, as viral particles generally lack these host-derived markers (Zhang et al., 2021). Additionally, combining nanoparticle tracking analysis (NTA) with transmission electron microscopy (TEM) and Western blotting for both exosomal and viral proteins provides crucial characterization to distinguish between the two populations (Thery et al., 2018; Chaudhari et al., 2022). Recent advances include the use of size exclusion chromatography (SEC) combined with immunoaffinity capture, which has demonstrated improved purity and yield of exosomes isolated from virus-infected cultures by efficiently removing contaminating virions and protein aggregates (Boing et al., 2014). Using approaches such as density gradients or immunoaffinity capture will also help isolate more homogeneous EV populations, such as viral genome–containing EVs or viral protein-containing EVs, leading to distinct functional outcomes.

In this scenario, scaling engineered exosomes for clinical applications presents substantial challenges in production, isolation, and purification (Chen and Li, 2025). Despite advances in exosome engineering, large-scale translation remains hindered by low yields, batch-to-batch variability, and limited reproducibility resulting from the intricate manipulation of donor cells and the heterogeneity of vesicle populations (Chen and Li, 2025). Conventional isolation methods, such as ultracentrifugation, size exclusion chromatography, and immunoaffinity capture, are labor-intensive, time-consuming, and often compromise vesicle integrity. Ensuring consistent cargo loading, biological activity, and sterility under Good Manufacturing Practice (GMP) conditions further complicates scale-up. Moreover, the lack of standardized potency assays and incomplete regulatory frameworks impede industrial adoption (Wang et al., 2025). Overcoming these barriers will require the integration of automated bioreactor platforms, quality control systems, and globally harmonized standards to enable the scalable, safe, and clinically reliable production of engineered exosome therapeutics (Palakurthi et al., 2024). These combined strategies are essential for accurately studying the role of exosomes in viral infection and transmission.

1.2. Exosomes main characteristics

Once considered merely cellular debris, exosomes are now recognized as key mediators of intercellular communication. They influence various signaling pathways, contribute to the maintenance of tissue homeostasis, and can promote pathological alterations in recipient cells (Hessvik and Llorente, 2018). The biogenesis of exosomes is a highly regulated and intricate process involving multiple molecular pathways. Although the precise mechanism underlying exosome biogenesis and release remain incompletely understood, several models have been proposed. These include both endosomal sorting complex required for transport (ESCRT)-dependent (Colombo et al., 2014) and ESCRT-independent pathways (Krylova and Feng, 2023).

It is widely accepted that members of the ESCRT machinery play a pivotal role in the biogenesis of exosomes (Gurung et al., 2021). The ESCRT system consists of five core complexes: ESCRT-0, ESCRT-I, ESCRT-II, ESCRT-III, and the vacuolar protein sorting-associated protein 4 (Vps4). ESCRT-0 initiates the process by recognizing and clustering ubiquitinated proteins on the endosomal membrane. ESCRT-I and ESCRT-II then drive the membrane budding process, facilitating the inward deformation of the endosomal membrane around the cargo. ESCRT-III is subsequently responsible for membrane scission, enabling the formation of intraluminal vesicles (ILVs) within multivesicular bodies (Hurley, 2015). One key member of ESCRT-0, hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), recruits tumor susceptibility 101 (TSG101), a key ESCRT-I protein required for exosome secretion. The subsequent recruitment of ESCRT-III is facilitated either by ESCRT-II or the ESCRT-III-associated protein ALIX (ALG-2-interacting protein X), which further promotes ILV formation and their separation from the MVB membrane (Heidarzadeh et al., 2021). Finally, the ESCRT machinery is disassembled and recycled through the action of Vps4, an ATPase that catalyzes the release of ESCRT components from the membrane (Tan et al., 2015; Hurley and Hanson, 2010).

Interestingly, several studies have demonstrated that exosome biogenesis can proceed even in the absence of key components from all four ESCRT complexes, suggesting the existence of ESCRT-independent mechanisms. These alternative pathways include ceramide-enriched lipid microdomains and tetraspanin-mediated sorting, such as CD63-dependent pathways (Tschuschke et al., 2020). For instance, in oligodendrocytes, exosome secretion is facilitated through ceramide production, which promotes domain-induced membrane budding independently of the ESCRT machinery (Trajkovic et al., 2008). Additionally, tetraspanin family proteins have been identified as critical regulators of ESCRT-independent exosome biogenesis. These proteins are involved in cargo sorting, membrane fusion, and membrane abscission during exosome formation and release (Andreu and Yanez-Mo, 2014; Hemler, 2008). Tetraspanins such as CD63 are highly enriched in ILVs and exosomes within MVBs (van Niel et al., 2011). CD63 promotes the sorting of melanosomal proteins into endosomes. CD81 is frequently found in exosomes and is hypothesized to contribute to the loading of specific ligands; however, direct evidence for its role in exosome biogenesis remains limited (Andreu and Yanez-Mo, 2014).

Fig. 1 summarizes the complexity of exosome biogenesis. The process begins with the formation of early endosomes (EE), which mature into late endosomes (LE). Within these compartments, inward budding of the endosomal membrane generates intraluminal vesicles, resulting in the formation of multivesicular endosomes. MVEs have two possible fates: they can fuse with lysosomes, leading to cargo degradation, or fuse with the plasma membrane, releasing ILVs as exosomes into the extracellular space. Exosome biogenesis can occur through two main mechanisms: the ESCRT-dependent pathway, which relies on ESCRT-0, I, II, III, and accessory proteins such as TSG101) to drive cargo selection and vesicle formation, and the ESCRT-independent pathway, which involves lipids such as sphingomyelin, ceramide, cholesterol, and structural proteins like tetraspanins (CD9, CD63, CD81). Once released, exosomes can be taken up by recipient cells, where they deliver proteins, nucleic acids, and lipids, thereby modulating signaling pathways, immune responses, and disease processes.

The molecular content of exosomes, including proteins, lipids, and various RNA species, has been cataloged in publicly available databases such as Vesiclepedia and ExoCarta. The structural features of exosomes are summarized in Fig. 2. The exosome is depicted as a lipid bilayer vesicle enriched with lipids such as cholesterol, sphingolipids, and sphingomyelin, which provide stability and regulate membrane dynamics. Embedded within the membrane are characteristic proteins, including tetraspanins (CD9, CD63, CD81), integrins, and receptors that mediate cell targeting and uptake. Inside the vesicle, several proteins are shown, such as Alix, TSG101, Hsp70, and Hsp90, which are involved in exosome biogenesis, cargo sorting, and stress responses. The lumen also carries a variety of nucleic acids, including microRNAs (e.g., miR-3180-3p, miR-1246, miR-21-5p), messenger RNAs, and other RNA species, which can regulate gene expression in recipient cells. Additionally, exosomes may transport DNA fragments, signaling molecules, and transporters that contribute to intercellular communication. Together, these components illustrate the multifunctional nature of exosomes as carriers of lipids, proteins, and genetic material, enabling them to influence diverse physiological and pathological processes. Exosomes are characterized as single-membrane vesicles that carry a variety of lipids from their parent cells. Notably, the levels of phosphatidylcholine (PC) are relatively reduced in exosomes compared to their cells of origin (Doyle and Wang, 2019). In contrast, exosomes are significantly enriched in specific lipids, such as cholesterol, sphingomyelin, glycosphingolipids, and phosphatidylserine (PS), with concentrations elevated by approximately 2- to 3-fold relative to the originating cells (Pegtel and Gould, 2019).

Fig 2 — **Exosome structure**. An illustrative representation of exosome structure, highlighting the lipid bilayer membrane, embedded transmembrane proteins, and the internal content, such as proteins, nucleic acids, and lipids. Created in BioRender. Zannella, C. (2025) https://BioRender.com/ct0aqvu.

While the externalization of PS on the outer leaflet of the cell membrane is commonly recognized as a hallmark of apoptosis, emerging evidence suggests that PS can also be present on the surface of certain exosomes, as demonstrated by annexin-V binding assays (Buzas et al., 2018). This observation implies that PS translocation to the exosomal membrane may be influenced by the cellular origin and the physiological or pathological conditions under which the exosomes are secreted (Buzas et al., 2018). In addition to their lipid components, exosomes encapsulate a wide range of protein and nucleic acids. The protein cargo of exosomes participates in diverse biological processes such as cell adhesion, membrane trafficking, immune modulation, and signal transduction. Key components of exosomes include evolutionarily conserved proteins such as GTPases, actin/myosin, tubulin, and annexin, as well as proteins specifically associated with exosome biogenesis and functionality (Doyle and Wang, 2019). Proteins involved in MVB formation, such as ALIX, and heat shock proteins like HSC70 and HSC90, are commonly present. In addition, tetraspanins, like CD9, CD63, CD81, and CD82, play critical roles in exosome formation, cargo sorting, and functional delivery to recipient cells. Among these, CD9, CD63, and CD81 are widely recognized as canonical exosomal markers, frequently used for exosome identification and characterization (Mathieu et al., 2021).

Exosomes also carry genetic material, including mRNA, miRNA, and ncRNA (Valadi et al., 2007). The discovery of RNA-containing exosomes in 2007 revolutionized the field of intercellular communication, revealing their potential in gene silencing, biomarker discovery, and therapeutic applications (van Niel et al., 2018). Later, in 2014, double-stranded DNA (dsDNA) was also identified within exosomes (Peng et al., 2023a), expanding their role in genetic information transfer and immune modulation.

Following their release into the extracellular environment, exosomes can be taken up by recipient cells via multiple mechanisms, including endocytosis, receptor–ligand interactions, and direct membrane fusion. A summary of these exosome uptake mechanisms is provided in Table 2 (Tian et al., 2013; Svensson et al., 2013; Mulcahy et al., 2014).

Table 2.

Mechanisms of exosome uptake into cells.

Mechanism	Description	Molecules/Proteins Involved	Cell Types	Conditions	Advantages/Limitations	References
Clathrin-mediated endocytosis	Receptor-dependent internalization via clathrin-coated pits	Clathrin, adaptins, dynamin	Many cell types	Presence of specific receptors for exosomal ligands	High specificity; saturable; receptor-expression dependent	(Mulcahy et al., 2014)
Caveolin-mediated endocytosis	Uptake via caveolae (cholesterol- and caveolin-rich invaginations)	Caveolin-1, cholesterol, dynamin	Endothelial and epithelial cells	Cholesterol-rich membrane domains	Selective uptake; inhibited by cholesterol depletion	(Mulcahy et al., 2014)
Macropinocytosis	Non-specific engulfment of extracellular fluid and vesicles	Actin, Rac1, PAK1, PI3K	Dendritic cells, cancer cells	Stimulated by growth factors and oncogenes	High capacity; low specificity	(Mulcahy et al., 2014)
Phagocytosis	Engulfment of large particles, including exosomes	Fc receptors, scavenger receptors, and actin	Immune cells (macrophages, neutrophils, dendritic cells)	Presence of opsonins or 'eat-me' signals on exosomes	Efficient in clearance; slower and less specific	(Feng et al., 2010)
Direct membrane fusion	Fusion of the exosomal membrane with the plasma membrane, releasing cargo into the cytosol	Fusogenic lipids (e.g., phosphatidylserine), SNARE proteins	Various cell types	Influenced by lipid composition and acidic pH	Rapid cargo release; limited to favorable conditions	(French et al., 2017)
Receptor-ligand interaction	Binding of exosomal surface proteins to target receptors, inducing uptake or signaling	Tetraspanins (CD9, CD63, CD81), integrins	Various target cells	Complementary receptor expression	Specific recognition can trigger signaling without uptake	( French et al., 2017)

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For instance, in the case of non-enveloped viruses such as Hepatitis A virus (HAV) and Hepatitis E virus (HEV), viral particles and associated factors—such as ALIX and tetraspanins—can be packaged into ILVs and released into the extracellular environment via fusion of MVBs with the plasma membrane. Interestingly, enveloped viruses like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus 1 (HIV-1) also utilize this pathway for egress, exploiting exosome-mediated release mechanisms. Viruses such as herpes simplex virus-1 (HSV-1) follow a different strategy. HSV-1 virion maturation occurs in the cytoplasm, with secondary envelopment taking place within trans-Golgi network (TGN)-derived vesicles (Turcotte et al., 2005). The virus is then released within shedding microvesicles. During this maturation process, viral components may become enclosed within exosomes, incorporated into exosomal membranes, or co-released during MVB–plasma membrane fusion. Specifically, for HSV-1, the glycoprotein B (gB) has been observed to accumulate at MVBs, where ubiquitination acts as a sorting signal for its inclusion (Calistri et al., 2007). Furthermore, exosomes released from HSV-1–infected cells have been reported to contain viral mRNAs and miRNAs (Kalamvoki et al., 2014).

Exosomes interact with recipient cells through a variety of mechanisms, including endocytosis, membrane fusion, and receptor-mediated signaling (Tian et al., 2013). These interactions can significantly influence host immune response by modulating transcriptional activity within recipient cells and impacting the dynamics of viral replication (Crenshaw et al., 2018). One critical mechanism involves the exosome-mediated activation of intracellular signaling pathways. Exosomal cargo can stimulate downstream kinases that inhibit IkB kinase (IKK) complexes, including IKKα/β and TANK-binding kinase 1 (TBK1) (Kalluri and LeBleu, 2020). This inhibition plays a significant role in regulating the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a a master transcription factor that governs inflammatory responses, antiviral defense, and immune homeostasis. Thus, viral infections can manipulate exosome content and signaling to suppress or alter host immune responses. By interfering with transcription factors such as NF-κB, viruses may enhance their own replication and evade immune detection, further contributing to disease pathogenesis (Fleming et al., 2014). Interestingly, certain viruses, such as the Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), both of which are associated with the development of various lymphoproliferative disorders, can alter the structural and molecular composition of exosomes, thereby modulating protein expression profiles and influencing cell survival and apoptosis (Anderson et al., 2018). Exosomes derived from latently infected B lymphocytes have been shown to contain protein cargo significantly enriched in molecules associated with viral latency, cell survival, and immune evasion. Remarkably, approximately one-third of the proteins identified in these exosomes are directly linked to processes related to latency maintenance, disease progression, and cell death regulation (Cai et al., 2016).

The precise mechanisms by which exosomes influence viral infection and replication remain incompletely understood. However, accumulating evidence indicates that viruses actively exploit exosomal pathways to enhance their survival and propagation within the host. This review aims to elucidate the key mechanisms underlying exosome-mediated viral transmission, with a particular focus on how viruses manipulate exosome biogenesis, cargo loading, and release to facilitate intercellular dissemination and immune modulation. Several reviews have previously addressed the general role of EVs in virology; however, most have focused either on a single viral family or primarily on human pathogens. The novelty of the present review lies in its comparative perspective across diverse human and animal viruses, its balanced emphasis on the dual role of exosomes in both promoting and inhibiting infection, and its focus on methodological standardization and emerging therapeutic applications.

2. Methodology

This review is based on a comprehensive literature analysis focusing on the role of exosomes in viral infections, to gain a deeper understanding of their involvement in viral pathogenesis and immune evasion. This study was designed as a narrative review with systematic search elements. We aimed to provide a comprehensive and integrative overview of the role of exosomes in viral infections, rather than to conduct a full systematic review or meta-analysis. A systematic search was conducted across multiple electronic, including PubMed, Google Scholar, Scopus, Science Direct, and the Web of Science, to ensure broad and informed coverage. To maximize the relevance and scope of the literature, the following keywords were used: “exosomes”, “exosomes and viral infection”, “role of exosomes in viral pathogenesis”, and “extracellular vesicles in viral infection”. Inclusion criteria were: (i) recent studies related to the structure and functional activity of viral exosomes; (ii) all experimental evidence linking exosomes to viral infection. Based on these criteria, a total of 269 articles published up to 2025 were identified as suitable. Of these, 200 articles were selected for in-depth review and critical analysis to construct a coherent and informative synthesis of the current knowledge in the field. Fig. 3 shows the PRISMA flowchart summarizing the study selection process, and the detailed PRISMA protocol is provided in the Supplementary Materials.

Fig 3 — **Schematic flow chart of study selection process**. Created in BioRender. Zannella, C. (2025) https://BioRender.com/otv5cih.

3. Role of exosomes in human and animal infectious diseases

Enveloped viruses

3.1. Role of exosomes in HIV infection

HIV primarily targets the cellular immune system, infecting CD4⁺ T helper (Th) lymphocytes, CD4⁺ macrophages, and select populations of dendritic cells. The progression of infection leads to Acquired Immunodeficiency Syndrome (AIDS), a condition characterized by a marked depletion of CD4⁺ T cell counts, resulting in immunosuppression and increased vulnerability to opportunistic infections (Rezaie et al., 2021).

Notably, exosomes derived from HIV-infected cells were among the first virus-associated exosomes to be isolated and characterized. In 2006, the "Trojan exosome hypothesis" was proposed, suggesting that retroviruses, including HIV, may hijack the exosomal biogenesis pathway to acquire their envelope and facilitate receptor-independent infection of target cells (Gould et al., 2003). This concept has significantly influenced HIV research by revealing novel mechanisms of viral dissemination and shaping the development of new antiretroviral therapeutic strategies.

The biogenesis of HIV-associated exosomes is a multi-step process intricately connected to the viral replication cycle and host intracellular trafficking pathways, as illustrated in Fig. 4.

As shown in Fig. 4, HIV begins its replication cycle by binding to the CD4 receptor and co-receptors such as CCR5 on the surface of a host cell, typically a CD4+ T lymphocyte. Following this attachment, the viral envelope fuses with the cell membrane, allowing viral RNA and enzymes to enter the cytoplasm. Through reverse transcription, the viral RNA is converted into double-stranded DNA, which is then transported into the nucleus and integrated into the host genome by the viral integrase enzyme, forming a provirus. This integrated DNA is transcribed into various RNA species, including mRNA for viral protein synthesis, regulatory RNAs, and genomic RNA for packaging. The mRNAs are translated by ribosomes in the rough endoplasmic reticulum, producing viral proteins that undergo post-translational modifications (PTMs) in the trans-Golgi network to ensure proper function. These components are then directed to multivesicular bodies (Patters and Kumar, 2018), where viral RNA and proteins come together. MVBs formation occurs through either ESCRT-dependent or ESCRT-independent pathways, and their subsequent fusion with the plasma membrane results in the release of exosomes into the extracellular milieu. This process is tightly regulated by host Rab GTPases and SNARE proteins, demonstrating the intricate coordination between viral components and host cellular machinery (Martin-Jaular et al., 2021). During HIV infection, exosomes may exert dual role, a pathogenic or a protective one. This duality likely arises from a complex interplay of factors, including the specific viral and host-derived components contained within the exosomes and the physiological context of the infected or recipient cells.

3.1.1. Proviral effects of EVs in HIV infection

During HIV infection, exosomes play a critical role by contributing viral dissemination and modulating host immune response (Rezaie et al., 2021). Exosomes released from HIV-infected cells can carry various viral components, including the negative regulatory factor (Nef) protein. Nef-containing exosomes have been shown to induce apoptosis in uninfected bystander cells, thereby weakening immune defenses and facilitating viral spread (Lenassi et al., 2010; Arenaccio et al., 2014). In addition to Nef, other HIV associated-proteins have been detected within exosomes, such as the viral capsid protein p24, the envelope glycoprotein gp120, and the transactivator protein Tat (Rahimian and He, 2016; Arakelyan et al., 2017). These proteins may influence recipient cell signaling, immune activation, and susceptibility to infection. Exosomes also encapsulate host-derived components relevant to HIV pathogenesis. For example, Fig. 4 also illustrates that an HIV-infected cell releases exosomes containing viral and host-derived components, such as transactivating response (TAR) RNA and chemokine receptors such as the C-C chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4), which serve as HIV co-receptors and may enhance viral tropism and cell-to-cell transmission (Wu and KewalRamani, 2006). These exosomes bud off from the infected cell and can be taken up by an uninfected recipient cell. Once delivered, the exosomal contents modulate the recipient cells environment by engaging toll-like receptors (TLRs) and activating NF-κB signaling pathways, thereby influencing immune responses and potentially priming the cell for subsequent HIV infection. When the exosomes deliver viral factors to uninfected recipient cells, they can significantly enhance the cell’s susceptibility to HIV infection. This process involves a complex interplay wherein the exosomal cargo primes target cells for infection by facilitating viral entry, promoting cellular activation, and supporting viral dissemination. EVs can contribute to HIV infection through the presence of specific surface molecules such as T-cell immunoglobulin and mucin domain-containing protein 4 (TIM-4). TIM-4, when present on EV membranes, facilitates the attachment and internalization of HIV-1 virions into host cells. This interaction enhances viral trafficking to immune cells, thereby increasing infection rates and potentially accelerating disease progression (Sims et al., 2017).

Moreover, recent studies have demonstrated that EVs can transport both host-derived and viral miRNAs that modulate the host immune response and promote HIV replication. HIV-infected macrophages release EVs containing miRNAs that inhibit the RNA interference machinery of recipient cells, thereby facilitating viral persistence (Roth et al., 2015). Notably, EVs enriched in HIV-derived miRNAs, such as vmiRNA88 and vmiRNA99, can trigger chronic immune activation by stimulating tumor necrosis factor (TNF)-α release from macrophages via Toll-like receptor 8 (TLR8) signaling (Bernard et al., 2014).

Exosomes also play a critical role in HIV dissemination and reactivation from latency. Both intact HIV virions and HIV-containing exosomes can be internalized by dendritic cells and subsequently transferred to CD4⁺ T lymphocytes via mechanisms known as trans-infection and trans-dissemination, respectively. It is important to note that the exosomes involved in trans-dissemination do not typically carry intact infectious virions. Instead, they are enriched in viral genetic material (primarily HIV RNA) and regulatory proteins such as Tat and Nef. This exosomal cargo can activate resting CD4⁺ T cells, making them more permissive to infection, and can also contribute to the reactivation of latent proviruses. In contrast, trans-infection refers to the transfer of complete virions from dendritic cells to CD4⁺ T lymphocytes, leading to productive infection. Chiozzini et al. demonstrated that trans-dissemination of exosomes from HIV-infected cells leads to activation of resting CD4⁺ T cells, facilitating efficient HIV trans-infection and viral gene expression in these target cells (Chiozzini et al., 2017). This process allows for HIV propagation and reactivation without inducing the cytopathic effects typically associated with direct DC infection (Kulkarni and Prasad, 2017).

3.1.2. Antiviral effects of EVs in HIV infection

Conversely, exosomes can also exert protective effects during HIV infection by carrying antiviral factors that inhibit viral replication. These include the cytidine deaminase APOBEC3G (A3G), interferon-stimulated genes, and specific host-derived microRNAs, all of which contribute to host innate immunity against HIV (Sadri Nahand et al., 2020). Notably, A3G-containing EVs have been shown to reduce HIV replication in recipient target cells, supporting their potential as natural antiviral agents. However, the biological relevance of A3G-EVs in vivo appears to be limited, primarily due to the low incorporation efficiency of A3G into EVs. This low affinity diminishes their overall impact on HIV restriction under physiological conditions (Dias et al., 2018).

Exosomes have also been shown to play protective roles against HIV infection, particularly through their content of antiviral proteins, interferon-stimulated genes (ISGs), and regulatory RNAs. For example, human brain microvascular endothelial cells (HBMECs), upon activation of Toll-like receptor 3 (TLR3), secrete EVs enriched in antiviral proteins and ISGs that can inhibit HIV replication in the central nervous system, potentially contributing to neuroprotection during HIV infection (Sun et al., 2016).

Similarly, intestinal epithelial cells stimulated via TLR3 release EVs containing miRNAs that suppress HIV-1 infection. These EVs have been shown to protect CD4⁺ T cells and macrophages in the gastrointestinal mucosa, a major site of early HIV replication and immune depletion (Guo et al., 2018).

In the context of vertical (mother-to-child) transmission, exosomes present in body fluids such as semen and breast milk have been observed to reduce the risk of HIV transmission. These exosomes interfere with the HIV life cycle, potentially through receptor decoy mechanisms or the delivery of inhibitory molecules (Naslund et al., 2014). Furthermore, T lymphocytes, including both CD4⁺ and CD8⁺ T cells, can secrete exosomes with anti-HIV functions. EVs expressing surface CD4 molecules may act as decoys, binding to HIV-1 virions and thereby protecting endogenous CD4⁺ T cells from infection (Chen et al., 2021). In addition, CD8⁺ T cell-derived EVs have been shown to contain antiviral proteins capable of suppressing HIV replication in infected cells (Tumne et al., 2009).

3.1.3. EVs' therapeutic application in HIV infection

Current antiretroviral therapies (ART) for HIV, while effective at suppressing viral replication, face significant challenges such as drug resistance, poor patient adherence, and adverse side effects, highlighting the need for novel and innovative therapeutic strategies (Rasmussen and Lewin, 2016). The discovery of biomarkers during ART holds significant promise for improving the clinical monitoring of HIV patients. Such biomarkers may enable the early detection of CD4⁺ T cell recovery following treatment initiation, serving as indicators of therapeutic response and immune restoration (Pacheco et al., 2015; Chehimi et al., 2007). Notably, studies have identified exosome-derived microRNA-192 (miR-192), interleukin-6 (IL-6), and soluble CD14 (sCD14) as potential biomarkers associated with initial CD4⁺ cell recovery after the commencement of ART. In contrast, exosomal miR-144 has been found to correlate with long-term CD4⁺ recovery, particularly after 96 weeks of therapy (Chehimi et al., 2007). Exosome-based delivery approaches have been investigated as potential strategies against HIV. Shrivastava et al. (Shrivastava et al., 2021) showed that exosomes could be engineered to carry therapeutic RNAs into HIV-infected cells, resulting in significant suppression of viral replication by epigenetic repression. More broadly, engineered vesicles and nanovesicles have been reviewed as promising platforms for delivering anti-HIV drugs and RNA therapeutics (Qiu et al., 2018). In addition to therapeutic applications, exosome-based vaccines have also been tested clinically: Andre et al. (Andre et al., 2004) that exosomes derived from dendritic cells pulsed with HIV peptides, which demonstrated safety and immunogenicity. Together, these studies highlight the potential of exosome engineering both as a delivery system for antiviral agents and as a vaccine platform against HIV. Beyond diagnostics, exosomes are emerging as innovative therapeutic tools, particularly in enhancing the efficacy of the "shock and kill" strategy for targeting latent HIV reservoirs (Nuhn et al., 2022). This strategy involves the use of latency-reversing agents (LRAs) to reactivate latent HIV ("shock"), followed by clearance ("kill") of the infected cells through immune responses or virus-induced cytotoxicity. Exosomes have shown potential as delivery vehicles for epigenetic modulators such as histone deacetylase inhibitors (HDACi), including valproic acid and vorinostat, which are crucial for reactivating latent HIV in immune cells (Chianese et al., 2021; Sherrill-Mix et al., 2013). As previously discussed, exosomes released from HIV-infected cells can also contribute to latent reservoir reactivation by delivering proteins such as ADAM17, TNF-α, Nef, and Tat to resting CD4⁺ T cells (Tang et al., 2018). This functional interplay among epigenetic regulation, immune modulation, and targeted delivery underscores the therapeutic promise of exosomes in reversing latency and promoting clearance of infected cells (Hong et al., 2017). Shrivastava et al. developed a novel approach for stable epigenetic repression of HIV using a zinc finger protein fused to DNA methyltransferase 3A (DNMT3A). This recombinant construct was packaged into exosomes for systemic administration and demonstrated the ability to achieve long-term silencing of HIV expression in infected mouse models, highlighting the feasibility of exosome-mediated epigenetic therapies (Shrivastava et al., 2021). In conclusion, EVs play a complex and dualistic role during HIV-1 infection, contributing to both viral persistence and antiviral defense. Multiple factors, including vesicle subtype, purity, cellular origin, and molecular cargo influence their impact. Further research is needed to unravel the fundamental regulatory mechanisms of EVs in HIV pathogenesis and to improve methodologies for EV isolation, characterization, and functional analysis.

3.2. Role of exosomes in HSV infection

HSV-1 is a double-stranded DNA virus classified within the Alphaherpesvirinae subfamily. It is most commonly associated with orofacial lesions, but, rarely, can also lead to severe infections, such as herpetic encephalitis, keratitis, and neonatal herpes. HSV-1 exploits host-derived exosomes for various aspects of pathogenesis, including immune evasion, viral replication, and virion egress (Kalamvoki et al., 2014). These vesicles carry a diverse array of viral and host-derived molecules, including mRNAs, miRNAs, ncRNAs, and proteins. Notably, they are enriched in tetraspanins such as CD9, CD63, and CD81, which are commonly associated with exosomal structure and function. In addition, exosomes derived from HSV-1–infected cells have been shown to contain key innate immune components, such as the stimulator of interferon genes (STING), suggesting a role in modulating antiviral signaling pathways (Kalamvoki et al., 2014). Here, we summarize the critical contributions of EVs in the context of HSV-1 infection, highlighting their involvement in viral propagation, immune regulation, and host-pathogen interactions.

3.2.1. EVs roles in HSV replication and egress

The biogenesis of HSV-1-associated exosomes involves significant modulation of host cellular machinery to facilitate viral propagation. Exosomes from HSV-1-infected cells are enriched in the tetraspanin CD63 (Kalamvoki et al., 2014), while a reduction in intracellular CD63 levels correlates with enhanced extracellular secretion, suggesting that HSV-1 actively stimulates CD63 exocytosis to promote the export of viral and host factors beneficial for its replication (Concha et al., 2024). In addition, Rab27 has been detected in exosomes from HSV-1-infected oligodendrocytic cells. Functional studies have shown that silencing Rab27 leads to impaired viral replication and a reduction in plaque size, emphasizing its critical role in the HSV-1 life cycle and pathogenesis. Other host factors also contribute to the egress of both exosomes and viral particles. Notably, heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) has been identified as a key regulator in the release of exosomes and HSV-1 virions from infected cells, highlighting its dual role in both RNA processing and vesicular trafficking (Zhou et al., 2020).

3.2.2. EVs impair the host immune response in HSV infection

Exosome cargo plays a key role in modulating the immune response during HSV-1 infection. One prominent example is viral gB, which is rerouted into the exosome biogenesis pathway. This process hijacks the MHC class II antigen machinery, specifically disrupting the endosomal sorting and surface trafficking of Human Leukocyte Antigen – DR isotype (HLA-DR) molecules (Grabowska et al., 2020). HSV-1 further enhances immune evasion, redirecting HLA-DR into exosomes, thereby preventing effective antigen presentation to CD4⁺ T cells (Temme et al., 2010; Bello-Morales and Lopez-Guerrero, 2018). Moreover, ubiquitination of gB promotes its overexpression, enriching exosomes with viral proteins and enhancing their immunomodulatory potential (McLellan, 2009; Muntasell et al., 2007). These gB-enriched exosomes, or gB/HLA-DR complexes, can be transferred to uninfected recipient cells, modulating their immune signaling capacity and modulating the host response to viral antigens (Temme et al., 2010). To sum up, Fig. 5 represents how HSV-1 exploits host cell mechanisms during infection. The virus, characterized by its envelope containing the viral gB protein, interacts with the host receptor HLA-DR on the cell surface to initiate entry. Following this interaction, the viral material is directed into intracellular vesicular compartments. The magnified inset highlights the molecular composition of these vesicles, showing that they are enriched with CD63, a marker of late endosomal membranes, along with complexes of gB protein bound to HDR. These gB/HLA-DR complexes suggest that HSV-1 not only utilizes host receptors for cell entry but also hijacks the vesicular trafficking system, incorporating both viral and host molecules into vesicles that facilitate viral spread and immune evasion.

Fig 5 — **HSV-1 influences the extracellular vesicles (EVs) pathway to enhance infection and/or evade the immune system**. It has been demonstrated that HSV-1 may manipulate the major histocompatibility complex (MHC) class II processing pathway by altering the endosomal sorting of human Leukocyte Antigen – DR isotype (HLA-DR), hijacking these molecules from normal transport pathways to the cell surface and diverting them into the exosome pathway. Glycoprotein B (gB)-DR complexes were detected in a post-Golgi compartment and exosomes, but no longer on the cell surface (Temme et al., 2010). Exosomes can transfer gB or gB/HLA-DR complexes to uninfected cells. Created in BioRender. Zannella, C. (2025) https://BioRender.com/l2h1so8.

In Herpes Simplex Encephalitis (HSE), exosomes have been implicated in triggering brain autoimmunity by presenting neuronal autoantigens on their surface (Li, Gu, et al., 2022). HSE is a severe neuroinflammatory condition caused by HSV-1 infection, primary affecting the temporal lobes and leading to inflammation, neuronal injury, and, in some cases, autoimmune complications. Neurons damaged by HSV-1 may package intracellular brain antigens, such as the N-methyl-D-aspartate (NMDA) receptor, the γ-aminobutyric acid-B (GABAB) receptor, and some miRNAs including miR-H2-3p and miR-H4-3p, into exosomes. These vesicles are then released into the extracellular space, where they can interact with immune cells at sites of inflammation or circulate to peripheral tissues. Upon uptake by antigen-presenting cells, such as dendritic cells (Armangue et al., 2014), these exosome-associated brain antigens are presented to T cells, initiating an autoimmune response. This can result in the production of autoantibodies, including anti-NMDAR antibodies, which have been detected in some patients following HSE (Li et al., 2022). The presence of such antibodies may contribute to the development of autoimmune encephalitis (AE), a potentially severe post-infectious complication of HSV-1–mediated neuronal damage (Li et al., 2022).

3.2.3. EVs deliver antiviral molecules in HSV infection

Exosomes released by HSV-1–infected cells can serve as vehicles for the transfer of both viral components, such as viral mRNAs and miRNAs, and host-derived antiviral factors, such as STING (Tran et al., 2013). Importantly, exosomes from HSV-1–infected cells carry viral mRNAs that are not infectious by themselves, as they do not represent complete viral genomes. Rather, these transcripts are full-length or fragmented viral RNAs that may act as regulatory molecules in recipient cells, modulating host signaling pathways, immune responses, and potentially priming the cellular environment for subsequent HSV-1 infection (Kalamvoki et al., 2014). STING is a critical adaptor protein in the cytosolic DNA-sensing pathway, which triggers IFN-1 production and initiates downstream innate immune responses in recipient cells. The exosomal export of STING from infected to uninfected cells has been proposed as a host-mediated antiviral strategy to activate IFN signaling in neighboring cells, thereby limiting viral spread and restricting HSV-1 virulence (Kalamvoki et al., 2014). Interestingly, this mechanism may represent a balanced interaction wherein HSV-1 modulates its own dissemination: minimizing cytopathic damage and immune detection at the local level, while preserving the ability to spread systemically and potentially between hosts.

3.2.4. EVs microRNA conflictual role in HSV infection

Interestingly, exosome-derived miRNAs have a dual role in viral infections, boosting or suppressing HSV-1 replication (Mao et al., 2023). For instance, Wang et al. demonstrated that miRNAs delivered via exosomes can modulate viral replication without requiring gene deletion or mutagenesis, highlighting the utility of exosomal miRNAs as modulators of viral replication and as therapeutic tools (Tran et al., 2013). Of note, both viral and host-derived miRNAs can be selectively packaged into vesicles. A recent study analyzing exosomes from the cerebrospinal fluid (CSF) of HSV-1 encephalitis patients reported the presence of both viral and host-derived miRNAs. Specifically, HSV-1–encoded miRNAs such as miR-H27, miR-H3, and miR-H4 were identified alongside cellular miRNAs including miR-155-5p, miR-21-5p, miR-146a-5p, and miR-138-5p. Interestingly, increased levels of the host-derived miR-155-5p correlated with oxidative stress markers such as IL-8, linking exosomal miRNA cargo to host inflammatory responses (Scheiber et al., 2024). Earlier, Huang et al. described that a specific HSV-1–encoded miRNA, miR-H28, is selectively packaged into exosomes and transferred to recipient cells, where it modulates viral replication (Huang et al., 2019).

In herpesvirus infections, exosomes play a multifaceted role—on one hand, they assist in viral dissemination by transporting viral components between cells; on the other, they participate in shaping the host immune response, either by promoting immune evasion or by triggering antiviral defenses. This complex interplay highlights the dual functionality of EVs in viral pathogenesis and immune regulation. Future research should aim to elucidate the mechanisms by which HSV-1 exosomes mediate infection of neighbouring cells, promote viral persistence through the regulation of viral protein expression, and selectively traffic molecular cargo to facilitate viral dissemination. In-depth investigations into exosomal pathways involved in immune evasion, protein trafficking, and antigen presentation will be essential for unraveling the complex host–virus interactions that underpin HSV-1 pathogenesis. These insights may pave the way for the development of novel antiviral strategies targeting exosome-mediated processes.

3.3. Role of exosomes in Epstein-Barr virus (EBV) infection

EBV infects more than 90% of the global population and is and is the primary cause of infectious mononucleosis. Beyond its acute clinical manifestations, EBV has been extensively studied for its oncogenic potential, particularly its role in the development of various lymphoid and epithelial malignancies. These include nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL) (Zhang et al., 2015; Nanbo et al., 2013).

3.3.1. EVs in EBV-associated cancer progression and immune modulation

EBV-associated exosomes are predominantly found in infected cells and play a crucial role in manipulating the tumor microenvironment to promote tumor growth, immune evasion, and cell survival (Ito et al., 2021). The composition of exosomal cargo significantly differ between virally infected and non-infected (healthy) conditions, reflecting the pathogen-driven remodeling of host vesicle secretion (Canitano et al., 2013).

As detailed illustrated in Fig. 6, Epstein–Barr virus is strongly associated with the development of multiple malignancies, including nasopharyngeal carcinoma, gastric carcinoma (GC), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL), and one of the key mechanisms by which it contributes to tumorigenesis involves the release of exosomes from infected cells. These nanometer-sized extracellular vesicles, derived from the endosomal system, encapsulate a wide array of viral components that influence the tumor microenvironment and the immune system, including the viral latent membrane proteins LMP-1 and LMP-2A, which can mimic constitutively active receptors to promote cell survival, proliferation, and signaling through pathways such as NF-κB and PI3K/Akt; EBV-encoded small non-coding RNAs (EBERs), which act as pathogen-associated molecular patterns (PAMPs) to stimulate inflammatory responses and modulate innate immunity; viral mRNAs and miRNAs that can be translated or regulate host and viral gene expression, respectively; and a unique cluster of EBV-derived microRNAs known as BamHI fragment A rightward transcripts (BART miRNAs), which are highly abundant in EBV-associated epithelial tumors and play a central role in silencing host immune regulators, apoptotic pathways, and tumor suppressor genes.

Collectively, these exosome-packaged viral factors are efficiently taken up by neighboring uninfected or partially transformed cells, thereby extending EBV oncogenic influence beyond directly infected cells, reshaping the tumor microenvironment to favor angiogenesis, invasion, and metastasis, and ultimately driving cancer progression (Keryer-Bibens et al., 2006; Yang and Robbins, 2011; Iwakiri and Takada, 2010).

NPC-derived exosomes play critical roles in immune evasion, thereby promoting tumor survival and progression in the context of EBV-associated malignancy (Ko, 2015; Pattle and Farrell, 2006). These exosomes are enriched with hypoxia-inducible factor-1a (HIF1a) and latent LMP-1, both of which to facilitate tumor growth, angiogenesis, and cellular transformation under the hypoxic conditions typical of solid tumors (Aga et al., 2014; Mrizak et al., 2015). In addition, EBV-infected cells secrete exosomes containing EBER-1 and EBER-2, which are are complexed with the lupus antigen (La) ribonucleoprotein, as demonstrated by Ahmed et al. (Ahmed et al., 2018). While the precise mechanisms governing the nuclear export, cytoplasmic trafficking, and exosomal loading of EBERs remain unclear, their release into the extracellular space suggests a role in intercellular communication. Although the functional impact of EBER-containing exosomes on adjacent recipient cells is not yet fully understood, emerging evidence indicates they may activate TLR3, thereby enhancing innate immune responses and contributing to chronic inflammation (Iwakiri et al., 2009). Further studies are needed to dissect the immunopathological consequences of exosomal EBER transfer in EBV-associated cancers.

EBV pathogenesis and persistence are increasingly recognized to be mediated by exosomal transfer of viral mRNAs and miRNAs (Yang and Robbins, 2011). Notably, mature EBV-encoded miRNAs from EBV-transformed lymphoblastoid cell lines (LCLs) have been detected within recipient dendritic cells, thereby contributing to immune evasion and latent infection maintenance (Pattle and Farrell, 2006).

Among these miRNA, the BamHI fragment A rightward transcript (BART) family plays a pivotal role. Exosomes derived from EBV-infected cells deliver BART miRNAs to macrophages, where they induce the expression of immune-modulatory genes such as interleukin (IL)-10, TNF-α, and arginase-1, promoting an immunosuppressive phenotype (Nagpal et al., 2021). In addition to viral RNAs, EBV-derived exosomes carry host proteins such as cyclophilin A (CYPA), an immunophilin currently under investigation as a non-invasive biomarker for EBV-associated NPC (Liu et al., 2019).

In oral squamous cell carcinoma (OSCC), EBV-associated exosomes carrying EBER-1 have been shown to activate the retinoic acid-inducible gene-I (RIG-I) pathway in macrophages in vitro (Burassakarn et al., 2021). This activations leads to the release of immunosuppressive factors, such as indoleamine 2,3-dioxygenase (IDO), through IL-6 and TNF-α-dependent mechanisms, ultimately fostering an immunosuppressive microenvironment that dampens T cell-mediated immunity (Burassakarn et al., 2021).

Moreover, in vitro studies using gastric cancer cell lines with and without recombinant EBV infection revealed that EBV infection results in increased exosome release and enhanced expression of tetraspanins CD63 and CD81, as well as miR-155 in recipient epithelial cells. These findings suggest an EBV-mediated upregulation of exosomal trafficking and immune modulation within the tumor microenvironment (Kim and Kim, 2023; Hinata et al., 2020).

3.3.2. EVs in EBV-associated cancer therapies

EBV-containing exosomes, which carry EBV-derived molecules (such as viral miRNAs, transcripts, or proteins), hold significant potential for the development of biomarkers and anticancer therapies. Notably, exosomes derived from Vδ2-T cells have demonstrated antitumor activity against EBV-associated malignancies. These exosomes are enriched with death-inducing ligands such as Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL), along with natural killer (NK) cell-activating receptors like NKG2D, immunostimulatory ligands (CD80 and CD86), and antigen-presenting molecules including MHC class I and II (Wang et al., 2020). Functionally, these Vδ2-T cell–derived exosomes have been shown to efficiently induce apoptosis in EBV-associated tumor cells via the FasL and TRAIL pathways. Moreover, they enhance the expansion of EBV-specific CD4⁺ and CD8⁺ T cells in both in vitro and in vivo models, highlighting their promise as a dual-action therapeutic platform that combines direct tumor cytotoxicity with adaptive immune activation. Given their ability to carry immune-regulatory and tumor-modulating molecules, EBV-containing exosomes may play a pivotal role in modulating the immune response against EBV-associated malignancies (Chen et al., 2022; Cone et al., 2019). Consequently, integrating exosome profiling with existing non-invasive diagnostic approaches, such as cancer antigen screening and magnetic resonance imaging (MRI), could enhance the specificity and sensitivity of cancer detection—particularly in EBV-related malignancies. However, despite their potential, research on the therapeutic and diagnostic applications of EBV-associated exosomes remains limited. Further studies are needed to clarify their mechanistic roles, assess their clinical utility in anticancer therapy, and explore their involvement in other EBV-related and virus-associated cancers.

3.4. Role of exosomes in Coronaviruses (CoV) infection

The Coronaviridae family, comprising single-stranded positive-sense RNA viruses, is responsible for a broad spectrum of respiratory, gastrointestinal, and neurological disorders in humans and other animals. The most recently identified member, SARS-CoV-2, causes COVID-19, a pneumonia-like disease that emerged in December 2019 and rapidly escalated into a global pandemic, posing an unprecedented public health challenge (Gurunathan et al., 2021).

In the context of SARS-CoV-2 infection, exosomes act as carriers of viral components and mediators of intercellular communication. These nanoscale membrane vesicles are involved in various aspects of COVID-19 pathogenesis, including viral spread, inflammation, coagulopathy, and immune responses (Chen et al., 2022; Sur et al., 2021; Veit et al., 2022). SARS-CoV-2 primarily targets alveolar type II epithelial cells in the lungs, which express high levels of the angiotensin-converting enzyme 2 (ACE2) receptor (Zou et al., 2020). Viral entry occurs via the ACE2 receptor or through transmembrane protease serine 2 (TMPRSS2)-mediated pathways, followed by replication in perinuclear organelles, viral assembly in the ER-Golgi intermediate compartment (ERGIC), and release via vesicular transport. Simultaneously, exosomes containing both viral and host-derived components are released from infected cells, facilitating intercellular communication and potentially contributing to systemic disease manifestations (D'Avila et al., 2024). The detailed process of SARS-CoV-2 replication and exosome release from infected cells is illustrated in Fig. 7. In detail, the process begins with viral entry, which occurs either through TMPRSS2-mediated membrane fusion (step 1) or ACE2-dependent endocytosis (step 2), leading to the internalization of the virus into early endosomes. Once inside the host cell, the viral genome undergoes uncoating (step 3), followed by transcription and translation in the cytoplasm (step 4), enabling the synthesis of viral proteins and replication of the viral RNA. Assembly of progeny virions takes place in the endoplasmic reticulum and Golgi apparatus (step 5), after which mature virions are formed and released. Importantly, alongside direct viral egress, part of the viral material—including proteins and RNA—is packaged into exosomes via the endosomal pathway, particularly through MVBsformation (step 4). These exosomes, which display a specific set of surface proteins such as MHC molecules, tetraspanins, ACE2, and flotillin, are secreted by exocytosis and subsequently taken up by recipient cells through clathrin-mediated endocytosis (step 6). Acting as carriers of viral cargo, exosomes facilitate the viral spread. The process of exosome formation and release shares notable similarities with the viral replication cycle. During SARS-CoV-2 infection, infected cells secrete exosomes enriched with viral RNA (fragments or transcripts), proteins, and various bioactive molecules, which may facilitate viral dissemination and modulate the host immune response (Hassanpour et al., 2020). These exosomes can exert dual effects on COVID-19 pathogenesis—either exacerbating disease progression or, conversely, contributing to antiviral defense mechanisms.

Fig 7 — **SARS-CoV-2 replicative cycle and exosomes release from the infected cell.** SARS-CoV-2 infection involves complex intercellular communication mediated, in part, by exosomes. Following viral entry via (1) TMPRSS2-mediated fusion or (2) ACE2-dependent endocytosis, viral replication occurs within specialized cytoplasmic structures. While newly assembled virions are released directly from the cell surface, (3) a portion of the viral components is also packaged into exosomes through the endosomal pathway, and (4) MVB formation. (5) These exosomes, displaying a distinct surface protein composition (including MHC, tetraspanins, ACE2, and flotillin), act as carriers of viral cargo, enabling communication between infected and uninfected cells. (6) These exosomes are internalized by recipient cells through clathrin-mediated endocytosis, potentially influencing both viral spread and the host's immune response. Created in BioRender. Zannella, C. (2025) https://BioRender.com/zm092s6.

Moreover, exosomes hold promise as noninvasive diagnostic biomarkers and as therapeutic delivery vehicles, capable of transporting biomolecules or drugs directly to target cells (Kushch and Ivanov, 2023).

3.4.1. EVs influence immune response during SARS-CoV-2 infection

Recent research has demonstrated the presence of SARS-CoV-2 RNA in exosomal cargo isolated from both critical and non-critical COVID-19 patients (Amundson et al., 2021). Proteomic analyses of these exosomes have identified proteins associate with molecular transport, complement activity, protease inhibition, extracellular matrix organization, and immune defence mechanisms (Amundson et al., 2021). Furthermore, plasma-derived exosomes from COVID-19 patients were found to contain SARS-CoV-2 double-stranded RNA (dsRNA), which promotes the release of inflammatory cytokines and chemokines by immune cells (Chen et al., 2022). These findings suggest that SARS-CoV-2 may exploit exosome-mediated endocytosis as a means of viral dissemination throughout the host (Barberis et al., 2021; Gambardella et al., 2023). Exosomes have also been implicated in transporting viral cargo from the lungs to distal organs, potentially contributing to the systemic manifestations of COVID-19 (Ahmed et al., 2021). Additionally, exosomes from infected cells can enhance viral spread while dampening immune cell responses, suggesting that inhibiting exosome or microvesicle uptake by neighboring cells may represent a promising therapeutic strategy for limiting viral propagation. Exosomes derived from lung epithelial cells exposed to SARS-CoV-2 non-structural proteins (NSP)-12 and -13 have been shown to induce pulmonary inflammation in murine models. These exosomes are readily taken up by lung macrophages, resulting in activation of the NF-κB signaling pathway and the subsequent production of various inflammatory cytokines, including TNF-α, IL-6, and IL-1β (Teng et al., 2021). This pro-inflammatory response also promotes apoptosis of lung epithelial cells, contributing to tissue damage and disease severity (Zani-Ruttenstock et al., 2021). The complex interplay between exosomes and COVID-19 extends beyond local inflammation to involve systemic immune modulation. Exosomes isolated from COVID-19 patients have been shown to induce inflammatory signaling in distant organs, suggesting a broader systemic impact (Zani-Ruttenstock et al., 2021; Sur et al., 2021). Moreover, proteomic and transcriptomic analyses indicate that these exosomes are involved in pathways related to complement activation, Fc-gamma receptor signaling, immunoglobulin synthesis, humoral immune response, and coagulation regulation. This highlights the multifaceted role of exosomes in mediating immune dysregulation and thrombo-inflammatory responses during SARS-CoV-2 infection.

3.4.2. EVs' therapeutic application in SARS-COV-2 infection

Mesenchymal stem cell (MSC) therapy has demonstrated significant immunomodulatory effects, including the induction of anti-inflammatory macrophages, regulation of T and B cell activity, and T cell inactivation. Due to these broad immunoregulatory capabilities, MSCs are considered promising candidates for the treatment of severe COVID-19 cases (Watanabe et al., 2019; Kojima et al., 2019; Jayaramayya et al., 2020; Akbari and Rezaie, 2020). Importantly, exosomes derived from MSCs have shown therapeutic potential in preclinical models of acute respiratory distress syndrome (ARDS) associated with COVID-19, indicating their capacity to mitigate inflammation and promote tissue repair (Kiaie et al., 2021). In addition to their therapeutic effects, exosomes are being explored as biomarkers for disease diagnosis and progression monitoring in COVID-19 patients (Aljuhani et al., 2023). Moreover, exosomes carrying ACE2 have been found to neutralize the virus by competitively binding to its spike protein, thereby preventing viral entry into host cells in both in vitro and ex vivo models. These findings suggest that ACE2-expressing exosomes may serve as a natural defense mechanism, potentially reducing viral load and disease severity (El-Shennawy et al., 2022; Kiaie et al., 2021). Novel exosome-based technologies are also being developed for the detection and diagnosis of SARS-CoV-2 infection, demonstrating the versatility of exosomes in both therapeutic and diagnostic fields (Happel et al., 2022). Wang et al. (Wang et al., 2022) designed exosomes decorated with a recombinant receptor-binding domain (RBD) of the Spike protein, administered intranasally, which elicited robust systemic and mucosal immune responses in preclinical models. More recently, Cacciottolo et al. (Cacciottolo et al., 2023) demonstrated that nanogram doses of Spike protein delivered via exosomes were sufficient to induce potent neutralizing antibody responses against both Delta and Omicron variants. In addition, bioengineered small EVs presenting multiple SARS-CoV-2 antigens were shown to stimulate strong humoral and cellular immunity (Jackson et al., 2024). These studies underscore the translational potential of engineered exosomes and exosome-mimetics as next-generation vaccine platforms for coronavirus infections, with advantages including low antigen dose requirements and the ability to elicit both systemic and mucosal protection. In conclusion, exosomes represent a multifaceted tool in the pathogenesis and management of COVID-19. Their roles in viral transmission, immune modulation, and potential for therapeutic and diagnostic applications underscore the urgent need of further investigation to fully harness their potential to counteract this global health crisis.

3.5. Role of exosomes in Flavivirus infection

Flaviviruses are a genus of enveloped, positive-sense single-stranded RNA viruses within the Flaviviridae family. Many of these viruses are arthropod-borne, primarily transmitted to humans through the bite of infected mosquitoes or ticks. Notable human pathogens in this group include Zika virus (ZIKV), Dengue virus (DENV), Yellow Fever virus (YFV), and West Nile virus (WNV) (Liang and Dai, 2024). ZIKV and DENV are of particular global health concern due to their widespread distribution, epidemic potential, and significant clinical manifestations. ZIKV is associated with congenital malformations and neurological complications, while DENV can cause dengue fever and severe dengue hemorrhagic syndromes. Both viruses replicate efficiently in mosquito vectors (Aedes aegypti and Aedes albopictus) and human hosts, with the virus–host interactions heavily influencing viral spread and disease severity (Liang and Dai, 2024). In the context of ZIKV and DENV, EVs play dual roles, acting as proviral factors by facilitating viral spread and immune evasion, and as antiviral mediators by activating host defense pathways (Latanova et al., 2024) (Martinez-Rojas et al., 2025).

3.5.1. EVs in human host: proviral and antiviral role

EVs derived from ZIKV-infected human cells can carry viral envelope (E) proteins and RNA that interfere with the host immune response. For example, EVs can shield viral antigens from neutralizing antibodies, effectively promoting viral spread and immune evasion (Zhao et al., 2023). Similarly, EVs released from DENV-infected cells transport viral components, including nonstructural proteins and microRNAs, which disrupt endothelial integrity and modulate immune pathways such as Toll-like receptors, NF-κB, and JAK-STAT, promoting inflammation and suppressing antiviral responses (Agudelo et al., 2025). Circulatory EVs from DENV patients can also induce immunoregulatory proteins PD-1 and CD44 expression in CD4⁺ T cells, contributing to T cell exhaustion, while autophagy-related vesicles facilitate viral transmission in dendritic cells (Kumari et al., 2025).

In some cases, EVs can also deliver viral RNA to immune cells, triggering interferon responses that limit viral replication. For example, EVs from ZIKV-infected cells can induce antiviral signaling in plasmacytoid dendritic cells, providing a host defense mechanism (Tiberti et al., 2025).

3.5.2. EVs in mosquito vector: proviral and antiviral role

EVs from infected Aedes mosquitoes' saliva often contain subgenomic flaviviral RNA (sfRNA), which suppresses the host innate immune response at the site of the bite. This suppression facilitates viral replication and enhances transmission efficiency of both ZIKV and DENV (Yeh et al., 2023). EVs also transport viral components that help the virus persist in mosquito tissues, supporting vector competence. While less studied, EVs released by mosquito cells under certain conditions may carry small RNAs (siRNAs) that activate antiviral pathways in neighboring mosquito cells, potentially limiting viral replication within the vector. This represents a regulatory mechanism that controls viral load in mosquitoes (Martinez-Rojas et al., 2020).

EVs may act as indicators for disease advancement or as potential therapeutic targets. Comprehending their simultaneous roles in promoting and inhibiting viral activity is essential for creating novel approaches to manage ZIKV and DENV infections.

Envelope and non-enveloped viruses of the same family

3.6. Role of exosomes in Hepatitis virus infection

There are five major hepatitis viruses responsible for the majority of viral hepatitis cases worldwide: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). While other hepatotropic viruses are still under investigation (Longatti 2015), these five remain the principal focus in clinical and virological research. Recent studies have revealed that HAV and HCV exploit exosomal pathways to facilitate viral transmission, while paradoxically also activating host immune responses (Qu et al., 2011; Li et al., 2005). This duality underscores the complex interplay between viral exploitation and host defense, wherein exosomes serve both proviral and antiviral functions. Specifically, these viruses have evolved strategies to hijack exosomal biogenesis and trafficking to evade immune surveillance and enhance intercellular spread. At the same time, the host immune system leverages exosomes as vehicles for the delivery of antiviral molecules, including cytokines, microRNAs, and interferon-stimulated genes (Shi et al., 2021). In detail, Fig. 8 depicts the role of exosomes in infections caused by three different hepatotropic viruses—HAV, HCV, and HBV—and how their exosomal cargo influences pathogenesis and immune responses. On the left, exosomes derived from HAV-infected cells are shown to contain both complete virions and foreign proteins, including the structural protein pX, which interacts with ALG-2 interacting protein X (ALIX), a critical factor in the ESCRT machinery responsible for vesicle biogenesis and release, thereby facilitating viral dissemination. In the center, exosomes associated with HCV infection are illustrated as carriers of viral RNA and proteins that stimulate plasmacytoid dendritic cells (pDCs), triggering the production of type I and type III interferons; although this represents an antiviral defense mechanism, it also contributes to persistent inflammation and progressive liver damage. On the right, HBV-related exosomes are represented as containing viral proteins such as the hepatitis B surface antigen (HBsAg) and the regulatory protein HBx; these components are capable of modulating the host immune system by specifically impairing natural killer (NK) cell cytotoxicity, thereby reducing antiviral defense and allowing viral persistence. The Fig. highlights how exosomes could shape viral pathogenesis, immune evasion, and disease progression.

Fig 8 — **Schematic representation of the effect of exosomes. 1**) Exosomes from HAV-infected cells contain virions and foreign proteins, including the structural protein pX, which interacts with ALG-2 interacting protein X (ALIX), a key component of the endosomal sorting complexes required for transport (ESCRT) machinery. 2) Exosomes in HCV infections promote the plasmacytoid dendritic cell (pDC) activation, leading to the production of type I and III interferons, which contribute to inflammation and disease progression. 3) HBV-associated exosomes contain viral proteins, including Hepatitis B surface antigen (HBsAg) and hepatitis B virus regulatory protein X (HBx), that impair natural killer (NK) cell functions. Created in BioRender. Zannella, C. (2025) https://BioRender.com/6uzfm86.

3.6.1. EVs role in Hepatitis egress

During HAV infection, exosomes play a central role in the secretion of virions and foreign proteins. This process is mediated by the HAV structural protein pX, which interacts with ALIX, a key component of the ESCRT machinery. This interaction facilitates the formation of quasi-enveloped HAV (eHAV) particles and the packaging of viral components into exosomes, allowing them to evade neutralization by anti-HAV antibodies (Fig. 7) (Shi et al., 2021).

Similarly, HBV and HDV virions have been found to associate with late endosomal membranes and large intracellular vesicular compartments, implicating the ESCRT machinery in viral envelopment. Disruption of ESCRT function significantly impairs viral budding and release, underscoring its critical role in the viral life cycle (Shi et al., 2021). In the case of HEV, Rab5 and Rab7 are essential for the transport of enveloped virions, suggesting a convergence between exosome biology and HEV egress (Shi et al., 2021).

In HBV infections, exosomes derived from chronic hepatitis B (CHB) patients and HBV-infected hepatocytes contain HBV DNA, Hepatitis B surface antigen (HBsAg), HBV X protein (HBx), and HBx mRNA (Yang et al., 2017; Sanada et al., 2017). These exosomal components are shielded from degradation by host nucleases and proteases, contributing to immune evasion and viral persistence (Kapoor et al., 2017). Furthermore, the tetraspanin protein CD63 has been found to colocalize with HBV proteins in HBV-expressing cells, suggesting a direct role in the formation and release of infectious viral particles via the exosomal pathway (Ninomiya et al., 2021).

3.6.2. EVs participate in Hepatitis infection and immune evasion

Exosomes play a multifaceted role in HAV infection and immune evasion. Costafreda et al. demonstrated that exosome fusion pathways facilitate HAV infection by utilizing two host lipid receptors: HAV cellular receptor 1 (HAVCR1), which binds phosphatidylserine (PS), and Niemann-Pick C1 (NPC1), which binds cholesterol (Costafreda et al., 2020). According to their model, HAVCR1 and NPC1 are essential for membrane fusion at late endosomes under acidic pH conditions, despite the absence of a viral envelope glycoprotein. This fusion event enables the capsid-free HAV RNA contained within the exosome lumen to enter the cytoplasm, bypassing lysosomal degradation and initiating viral replication (Costafreda et al., 2020).

In vivo, interferon receptor-deficient mice exhibit high susceptibility to HAV infection, mimicking human hepatitis A pathology and supporting the mechanistic pathways identified in vitro (Ahmad et al., 2023). In these models, clathrin-mediated endocytosis was shown to be the primary route by which HAVCR1 and NPC1 mediate the delivery of exosomal cargo from infected cells (Ahmad et al., 2023).

A similar scenario is observed in HCV infection, which, although often asymptomatic, is marked by hepatic inflammation due to type I/III interferon induction and plasmacytoid dendritic cell (pDC) activation (Fig. 7) (Longatti et al., 2015). Bukong et al. reported that circulating exosomes from HCV-infected patients are infectious and resistant to anti-HCV E2 antibodies (Bukong et al., 2014). These exosomes actively package HCV RNA at high levels and can infect hepatocytes via non-canonical, receptor-independent pathways (Seeger et al., 2020; Kerviel et al., 2021).

Additionally, HCV-derived exosomes can mediate immune suppression. They promote the expansion of myeloid-derived suppressor cells (MDSCs) by downregulating miR-124, a microRNA critical for T follicular helper (Tfh) cell differentiation and function (Wang et al., 2018a; Thakuri et al., 2020).

In the context of HBV infection, exosomes have been shown to impair natural killer (NK) cell functions, including IFN-γ production, cytolytic activity, and responsiveness to poly(I:C) stimulation (Wang et al., 2020). Mechanistically, HBV exosomes suppress pattern-recognition receptor (PRR) signaling, notably by downregulating RIG-I, leading to diminished NF-κB and p38 MAPK activation and weakened antiviral responses (Kar et al., 2023; Wu et al., 2024; Ma et al., 2024). This immunosuppressive environment is further enhanced by virus-induced transforming growth factor-beta 1 (TGF-β1), which promotes exosome uptake by NK cells while simultaneously blocking NK activation receptors such as NKG2D and 2B4 (Kar et al., 2023; Wu et al., 2024).

3.6.3. EVs enhance immune signaling against hepatitis

Despite being exploited by viruses for immune evasion, exosomes can also function as potent antiviral agents by amplifying immune signaling pathways and facilitating viral recognition. In the context of hepatotropic viral infections, hepatocyte-derived exosomes containing viral RNA or DNA can activate antiviral immune responses upon internalization by pattern recognition receptor (PRR)-expressing immune cells. This mechanism is particularly crucial given that many hepatitis viruses suppress innate immune detection within infected hepatocytes (Li et al., 2013a).

For example, during HCV infection, hepatocytes fail to produce IFN-α due to the cleavage of the mitochondrial antiviral signaling protein (MAVS) by the viral NS3/4A protease. However, liver-resident pDCs can sense HCV infection via exosomes containing HCV RNA. These exosomes activate endosomal TLR7 in pDCs, triggering robust type I IFN production. This indirect sensing mechanism explains the observed upregulation of interferon-stimulated genes (ISGs) in the liver despite the inability of hepatocytes to produce IFN-α (Li et al., 2005). Similarly, eHAV exosomes are internalized by pDCs and detected via TLR7, resulting in strong type I IFN responses, whereas naked HAV particles fail to elicit such immune activation (Shrivastava et al., 2016). Beyond innate immunity, exosomes also contribute to adaptive immune responses by enhancing DC maturation and antigen presentation. In HCV infection, exosomes containing HCV RNA promote TLR3-dependent maturation of conventional DCs, leading to upregulation of costimulatory molecules such as CD80 and CD86, which are crucial for effective T cell priming (Peng et al., 2023b). Similarly, during HBV infection, hepatocyte-derived exosomes carrying HBV DNA and HBsAg are recognized by endosomal TLR9 in DCs. This recognition facilitates viral antigen processing and presentation, thereby enhancing CD4⁺ and CD8⁺ T cell responses essential for viral clearance (Shi et al., 2021).

3.6.4. EVs carry antiviral molecules against hepatitis

Exosomes also act as vehicles for specific interferon-stimulated genes (ISGs), contributing to antiviral defense mechanisms. For instance, DDX60, a cytosolic RNA helicase, is transferred via hepatocyte-derived exosomes to natural killer (NK) cells, where it promotes the degradation of HBV RNA. Likewise, Tetherin (BST2), an ISG that inhibits the release of HCV particles, can be delivered to target cells through exosomes (Yin et al., 2022). In addition to proteins, exosomes carry antiviral miRNAs that modulate host and viral gene expression. Murakami et al. demonstrated that macrophage-derived exosomes enriched in miR-29 family members suppress HCV replication by targeting the SOCS1/STAT3 signaling pathway. Other host-derived miRNAs, including miR-192, miR-223, miR-125b, and miR-203, have been shown to inhibit HBV transcript levels and reduce antigen expression in hepatocytes (Murakami et al., 2012).

While numerous studies underscore the immune-suppressive roles of viral exosomes, others highlight their potential to expose viral signatures and trigger immune responses. This dichotomy underscores the context- and timing-dependent nature of exosome-mediated immune modulation. Whether viral packaging into exosomes represents a targeted viral strategy for immune evasion or is simply a byproduct of cellular stress remains a matter of ongoing investigation.

Future research should aim to elucidate the molecular mechanisms by which hepatitis viruses exploit exosomal pathways to establish persistent infections, evade innate and adaptive immunity, and contribute to disease progression. A deeper understanding of the virus–exosome–host immune interface could open new avenues for developing novel therapeutic and diagnostic strategies against hepatitis virus infections.

Non-enveloped viruses

3.7. Role of exosomes in Human papillomavirus (HPV) infection and cancer

Human papillomavirus (HPV), a non-enveloped, double-stranded DNA virus belonging to the Papillomaviridae family, is primarily transmitted through sexual contact and skin-to-mucosal interaction. Persistent HPV infection is a major etiological factor in the development of cervical, anal, and other anogenital cancers, as well as a subset of head and neck squamous cell carcinomas. Recent studies have demonstrated that exosomes play a critical role in modulating various stages of HPV infection and pathogenesis, influencing viral persistence, immune evasion, oncogenic transformation, and tumor progression (Sadri Nahand et al., 2020).

3.7.1. EVs immune modulation in HPV infection and tumor progression

Exosomes are involved in the progression and immune modulation of HPV infections and related cancers (Xu et al., 2022). Studies have shown that exosomes released from HPV-infected cells contain viral oncogenes, such as E6 and E7, which are crucial for HPV-induced tumorigenesis (Chiantore et al., 2016). These exosomes can also carry high-risk HPV DNA, serving as potential biomarkers for the early, non-invasive detection of HPV-associated cervical cancer (Maitra et al., 2024; Acevedo-Sanchez et al., 2021). Furthermore, HPV-associated markers, like HPV16E6 and HPV16E7 mRNAs, are exclusively expressed in exosomes derived from HPV-positive (HPV⁺) cells, enabling discrimination between HPV⁺ and HPV⁻ tumors (Ludwig et al., 2020).

Exosomes derived from HPV⁺ cells exert significant immunomodulatory effects that facilitate tumor progression. Experimental ex vivo models have demonstrated that HPV⁺ exosomes, which contain the E6 and E7 oncoproteins, can reprogram immune cells through mechanisms such as receptor–ligand interactions at the cell surface or the delivery of mRNAs, miRNAs, and other bioactive cargos to recipient cells. In HPV⁺ tumors, exosome uptake by human DCs induces notable transcriptional changes, suggesting that these vesicles influence DC function by transferring regulatory RNAs (Ludwig et al., 2018). Interestingly, while HPV⁺ exosomes were shown to promote DC maturation and did not suppress the expression of antigen processing machinery (APM) components in mature DCs, clinical data tell a more complex story.

Retrospective analyses of oropharyngeal cancer patients have revealed that HPV⁺ exosomes correlate with reduced CD4⁺ and CD8⁺ T cell activity, indicating a net immunosuppressive effect in vivo (Gorvel and Olive, 2023). Supporting this, HPV infection induces cervical cancer cells to secrete C-X-C motif chemokine ligand 10 (CXCL10), which enhances PD-L1 expression in fibroblasts via exosomal signaling, promoting immune evasion within the tumor microenvironment (Chen et al., 2021). Moreover, exosomes from HPV⁺ tumors influence immune cell interactions by modulating CD47, a “don’t eat me” signal that inhibits phagocytosis. This helps tumor cells evade immune clearance by macrophages and other phagocytes (Pai et al., 2019).

The altered exosomal microenvironment in HPV-related cancers is enriched with viral proteins and host-derived oncogenic factors, such as LMP1, Survivin, and OncomiRs, suggesting the role of exosomes as mediators of oncogenic cargo transfer to neighboring cells (Guenat et al., 2017). These modified exosomes contribute to immune suppression and tumor-promoting signaling, thereby supporting cancer progression. Two primary mechanisms have been proposed to explain the pro-tumorigenic role of exosomes: (i) a direct mechanism, wherein oncogenic factors are transferred intact to recipient cells, and (ii) an indirect mechanism, which alters the extracellular milieu in a way that fosters tumor growth and invasion (Chiantore et al., 2020). Exosomes derived from HPV⁺ cells contribute significantly to tumor progression by modulating the tumor microenvironment. They promote angiogenesis through the transfer of pro-angiogenic signaling molecules, thereby supporting tumor growth and vascularization (Bhat et al., 2021).

Fig. 9 represents the contribution of exosomes in cervical cancer development. At the top, HPV infection of epithelial cells in the cervix is shown, where the virus replicates and contributes to oncogenesis. In the lower section, HPV-infected cells secrete exosomes that encapsulate viral oncoproteins, specifically HPV16 E6 and HPV16 E7, which are highlighted in the magnified vesicle. These oncoproteins are known to interfere with critical host regulatory pathways: E6 promotes the degradation of the tumor suppressor protein p53, impairing apoptosis and DNA damage responses, while E7 binds and inactivates the retinoblastoma protein (pRb), leading to uncontrolled progression through the cell cycle (Xu et al., 2022; Ludwig et al., 2018). When packaged into exosomes, these viral oncoproteins can be delivered to neighboring cells, enhancing tumor growth. Additionally, in cervical carcinoma, HPV⁺ exosomes have also been implicated in tumor innervation, a process associated with enhanced disease progression and metastasis (Lucido et al., 2019). Furthermore, these vesicles play a crucial role in inducing epithelial–mesenchymal transition (EMT), a key step in cancer metastasis. For example, exosomal epidermal growth factor receptor (EGFR) has been shown to mediate HPV-induced EMT in non-small cell lung cancer (NSCLC) cells, suggesting a mechanistic link between HPV infection and cancer progression (Zhou et al., 2022).

3.7.2. EVs therapeutic application in HPV infection

Although the specific antiviral functions of EVs in HPV infection remain incompletely understood, emerging evidence suggests that EVs play a role in antiviral immunity (Wazny et al., 2024). A promising example involves exosomes loaded with the HPV E7 oncoprotein, which have demonstrated antitumor and immunostimulatory effects in preclinical models (Li et al., 2022). In a study by Jing Li et al., mice inoculated with E7-loaded exosomes exhibited a robust cytotoxic T lymphocyte (CTL) response, characterized by the activation of E7-specific CD8⁺ T cells that significantly suppressed tumor growth in vivo (Li et al., 2022). These findings suggest that exosomes can serve as natural nanocarriers for delivering viral antigens in an immunogenic form, highlighting their potential as an innovative therapeutic cancer vaccine platform for HPV-associated malignancies (Di Bonito et al., 2017). This evidence further underscores the dual role of exosomes in both promoting tumor progression and modulating immune responses (Kurywchak et al., 2018). Additionally, HPV⁺ head and neck squamous cell carcinoma (HNSCC)-derived exosomal miR-9 has been shown to induce macrophage polarization and enhance tumor radiosensitivity, further demonstrating the capacity of exosomes to modulate the tumor microenvironment and therapeutic outcomes (Tong et al., 2020). Overall, exosomes exert a complex influence on HPV infection and related pathologies by regulating viral oncogene expression, immune modulation, tumor microenvironment dynamics, and disease detection. Deciphering this intricate interplay is critical for advancing targeted therapies and diagnostic strategies, ultimately leading to more effective prevention and treatment of HPV-associated diseases.

3.8. Role of exosomes in animal viral infection

Enveloped viruses

Recent studies have demonstrated that several enveloped animal viruses utilize or interfere with the exosome biogenesis pathway to facilitate their replication and dissemination. Many of these viruses induce increased exosome secretion or manipulate exosomal content to support their life cycle. A notable example is bovine viral diarrhea virus (BVDV), a member of the Pestivirus genus in the Flaviviridae family. BVDV is a major pathogen in cattle, causing reproductive disorders such as reduced fertility, congenital malformations, stillbirths, and abortions (Aitkenhead et al., 2024). BVDV possesses a single-stranded, positive-sense RNA genome that encodes both structural and non-structural proteins. The structural proteins include the capsid protein (C) and three envelope glycoproteins, namely ERNS, E1, and E2, while the non-structural proteins are essential for viral replication and modulating virus-host interactions (Al-Kubati et al., 2021).

Liang et al. demonstrated that BVDV infection significantly increases the exosome release from bovine placental trophoblast (BTC) cells, as evidenced by elevated expression of the exosomal markers CD9, CD63, and TSG101 (Liang et al., 2024). The infection induces both necrosis and apoptosis, and triggers autophagy, leading to the production of exosomes that facilitate virus transport between placental cells. These exosomes play a critical role in enhancing viral transmission within placenta, enabling BVDV to cross the placental barrier and potentially infect the fetus. Importantly, because this mode of transmission occurs via intracellular vesicles, maternal antibodies, specifically those targeting the E2 envelope protein, are ineffective at neutralizing the virus, allowing it to evade immune detection and persist during pregnancy. Consequently, targeting autophagy or exosomal biogenesis pathways may represent a promising therapeutic strategy to limit BVDV transmission and pathogenesis. By disrupting the formation or release of exosomes, it may be possible to prevent placental viral spread and fetal infection, offering a novel approach to controlling BVDV-induced reproductive losses in cattle. Porcine epidemic diarrhea virus (PEDV) is the etiological agent of a highly contagious acute enteric disease that primarily affects neonatal piglets. Clinically, PEDV infection is characterized by vomiting, severe watery diarrhea, dehydration, and, in severe instances, high mortality rates. PEDV is a member of the Alphacoronavirus genus within the Coronaviridae family (Stincarelli et al., 2023) and possesses a positive-sense, single-stranded RNA genome that encodes 16 non-structural proteins and 4 structural proteins, including the spike (S) glycoprotein and the envelope (E) protein (Lin et al., 2022). In 2010, a highly pathogenic variant of PEDV emerged, resulting in widespread outbreaks with significantly increased morbidity and mortality among suckling piglets (Wang et al., 2018b). Ding et al. have demonstrated that PEDV hijacks the exosomal pathway to enhance viral propagation and evade host immune defenses. Specifically, exosome-derived from PEDV-infected cells exhibit exosomal markers such as ALIX, CD9, and CD63 (Ding et al., 2023), and were found to contain viral genomic RNA and nucleoprotein (NP), while lacking the S and matrix (M) proteins, confirming the lack of contaminated virions. Moreover, these exosomes were capable of mediating infection in both permissive and non-permissive cells and were resistant to neutralization by anti-PEDV antibodies. This suggests that PEDV leverages exosomes as carriers to facilitate immune evasion and intercellular viral transmission, thereby playing a critical role in the virus’s transmission and pathogenesis.

Feline coronavirus (FCoV) is another member of the Coronaviridae family that infects animals, primarily targeting the gastrointestinal tract of domestic cats. FCoV exists in two distinct biotypes: feline enteric coronavirus (FECV), which typically causes mild or subclinical intestinal infections, and feline infectious peritonitis virus (FIPV), a virulent variant responsible for feline infectious peritonitis (FIP), a severe, often fatal systemic disease, especially in young cats (Jaimes and Whittaker, 2018). Recent in vitro studies have shown that FCoV infection can alter exosome biogenesis, leading to changes in exosome size and cargo composition (Wijerathne et al., 2024). In this study, CRFK cells infected with FCoV exhibited changes in EV size distribution (mean sizes shifted from ∼131.9 nm in control to ∼143.4 nm at 48 h post-infection) and a marked increase in total protein content. Additionally, an upregulation of classical exosome markers (Alix, TSG101, CD63) was observed, as well as alterations in the levels of membrane traffic‐related proteins (flotillin, clathrin), adhesion molecules (CD29), viral‐host receptor/protease markers (ACE2, TMPRSS2), and immune signalling components (TLRs 3, 6, 7; TNF‐α). These alterations suggest multiple possible mechanistic implications: first, increased EV production and elevated protein cargo might reflect enhanced vesicle release as a response to cellular stress and viral manipulation of endosomal sorting complexes (ESCRT pathway). The upregulation of membrane trafficking proteins, such as flotillin and clathrin, further supports enhanced EV release or altered vesicle trafficking. Secondly, the enrichment of adhesion molecules (e.g., CD29) and viral entry‐associated protease markers could facilitate the interaction of FCoV‐modified EVs with target cells, potentially enhancing infectivity or modifying immune cell responses. Thirdly, changes in EV cargo of immune signaling molecules (such as TLRs and TNF‐α) point toward a role of EVs in modulating the inflammatory milieu during FIP (Wijerathne et al., 2025). While these findings significantly narrow the gap in our understanding of animal coronavirus EVs, key mechanistic gaps remain. For example, the functional effects of FCoV‐derived EVs on macrophage polarization, cytokine induction in vivo, or the kinetics of viral spread have not yet been clearly demonstrated. Further studies employing proteomic profiling, knockdown/overexpression of key cargo molecules, and in vivo animal models are needed to establish causality between altered EV cargo and pathogenesis in FIP.

Avian influenza virus (AIV) H5N1, a member of the Orthomyxoviridae family, possesses a segmented, single-stranded, negative-sense RNA genome. AIVs are broadly classified into high-pathogenicity (HPAIV) and low-pathogenicity (LPAIV) strains based on their virulence and clinical outcomes (Charostad et al., 2023). HPAIV H5N1 is particularly virulent, causing severe disease manifestations in poultry such as reduced egg production, respiratory distress, diarrhea, and sudden death. Outbreaks of H5N1 have led to substantial economic losses in the poultry industry and have raised public health concerns due to zoonotic transmission events with high morbidity and mortality rates in humans (Ng et al., 2008). Recent studies have demonstrated that exosomes derived from chickens infected with HPAIV H5N1 play a role in both immune activation and viral dissemination. These exosomes have been shown to stimulate the MAPK signaling pathway in recipient immune cells, leading to the production of IFN-α and IFN-β) and pro-inflammatory cytokines, including IFN-γ, IL-1β, and CXCL8. Furthermore, the presence of viral proteins, such as nucleoprotein (NP) and NS1, within exosomes and their successful transfer to uninfected cells suggest that these vesicles may contribute to immune modulation and enhanced viral spread (Hong et al., 2022).

Porcine reproductive and respiratory syndrome (PRRS), also known as blue ear disease, is a major swine illness characterized by reproductive failure in breeding stock and respiratory disease in pigs of all ages. The causative agent, PRRS virus (PRRSV), is an enveloped, single-stranded, positive-sense RNA virus belonging to the Arteriviridae family within the Nidovirales order, which also includes CoVs (Montaner-Tarbes et al., 2016). The PRRSV genome encodes seven structural proteins, GP2, GP3, GP4, GP5, M, E, and N proteins, and a set of non-structural proteins (NSP1-NSP12) involved in viral replication and modulation of the immune response (Music and Gagnon, 2010). Recent studies have shown that exosomes isolated from the serum of PRRSV-infected pigs contain classical exosomal markers CD63 and CD81, along with PRRSV RNA and viral proteins (Montaner-Tarbes et al., 2016). These exosomes facilitate viral dissemination and immune evasion, as they are not neutralized by virus-specific antibodies. Importantly, viral components (viral genomic/subgenomic fragments and viral proteins) have been detected in serum-derived exosomes even in the absence of detectable viremia, indicating that exosomes may serve as sensitive markers for identifying subclinical or silent infections. This finding highlights the potential utility of exosome-based strategies in vaccine development, early disease detection, and disease monitoring in swine populations.

African swine fever virus (ASFV) is a large, complex, double-stranded DNA virus from the Asfarviridae family and is the etiological agent of African swine fever (ASF), a highly contagious and often lethal disease in domestic and wild pigs (Li, Chen, et al., 2022). ASFV poses a severe threat to global swine industries due to its high mortality rate, lack of effective vaccines, and ability to evade immune responses. Recent research has demonstrated that exosomes isolated from ASFV-infected pigs express characteristic surface markers such as CD5, CD63, CD81, and CD163. These exosomes also contain ASFV proteins, many of which are associated with coagulation pathways, suggesting a possible role in the vascular and immune dysregulation observed during infection (Montaner-Tarbes et al., 2019). Further analyses of plasma-derived EVs demonstrated that ASFV infection alters the abundance of proteins involved in complement activation, platelet function, and vascular integrity, suggesting a possible link between EV cargo and the hemorrhagic manifestations of the disease (Xu et al., 2022). In addition, small RNA sequencing of serum-derived exosomes from infected animals revealed differential expression of host miRNAs targeting key signaling pathways, including TLR, MAPK, and mTOR, which may contribute to immune modulation and viral persistence (Truong et al., 2023). Taken together, these findings indicate that ASFV exploits EVs not only as vehicles for viral components but also as mediators of host response dysregulation, potentially exacerbating vascular pathology and immune evasion during infection.

Avian leukosis virus (ALV) is a retrovirus of the Alpharetrovirus genus that primarily infects chickens, causing neoplastic diseases such as lymphoid leukosis, immunosuppression, reduced egg production, and decreased overall flock performance. Among its subgroups, ALV subgroup J (ALV-J) is considered the most pathogenic, associated with myeloid leukosis and higher mortality in poultry populations. ALV infection represents a major concern in poultry health and economics due to direct clinical manifestations and vertical transmission from hens to offspring. Recent studies have demonstrated that exosomes play multiple roles in ALV infection. In ALV-J, exosomes derived from infected chicken embryo fibroblasts (DF-1 cells) have been shown to carry viral components such as gag and env proteins, as well as the immunosuppressive domain (ISD) of envelope transmembrane subunits. These exosomes exert dose-dependent effects on splenocytes: at low doses, they may activate immune responses, whereas at high doses, they contribute to immunosuppression (Wang et al., 2017). Chicken biliary exosomes also show antiviral potential: exosomes isolated from bile promote proliferation of CD4⁺ and CD8⁺ T cells and monocytes in the liver, and significantly inhibit replication of ALV-J in DF-1 cells (Wang et al., 2014). In macrophage cells (HD11) infected with ALV-J, exosomes have been profiled to identify differentially expressed genes and proteins involved in immune signaling, tight junctions, TNF signaling, and immune tolerance. These data suggest that exosomes may mediate both viral spread and modulation of immune responses, including suppression or tolerance in certain contexts (Ye et al., 2020). Moreover, for ALV-J, semen-derived EVs appear to have a role in vertical transmission: EVs isolated from ALV-J-infected rooster seminal plasma (SE-ALV-J) were shown to contain ALV-J RNA and partial viral proteins, and could infect hens upon artificial insemination, subsequently transmitting the virus to progeny chicks (Liao et al., 2022). Furthermore, in co-infection settings, ALV-J together with the Reticuloendotheliosis virus (REV) leads to synergistic increases in exosomal miRNAs; several miRNAs were identified whose levels are higher under co-infection compared to single infections, suggesting a possible mechanism whereby exosomes contribute to enhanced pathogenicity in co-infection settings (Zhou et al., 2018).

Non-enveloped viruses

Duck hepatitis A virus type 1 (DHAV-1) is a non-enveloped, single-stranded, positive-sense RNA virus belonging to the Picornaviridae family, genus Avihepatovirus. It is the major causative agent of duck viral hepatitis, an acute and highly contagious disease of young ducklings characterized by hepatic necrosis and hemorrhage, with high morbidity and mortality. DHAV-1 poses a significant threat to the duck industry worldwide due to its rapid transmission and devastating economic impact. Exosomes purified from DHAV-1-infected duck embryo fibroblasts (DEFs) were found to contain complete viral genomic RNA, specific viral proteins, and, in some cases, intact virions. These vesicles were capable of mediating productive infection in DEFs, duck embryos, and ducklings. Importantly, neutralizing antibodies that effectively block free DHAV-1 virions did not inhibit exosome-mediated infection, indicating that exosomes may function as a viral immune-evasion mechanism (Xu et al., 2023). These findings suggest that DHAV-1 hijacks the exosomal pathway to facilitate viral spread, protect viral components from host immune recognition and enhance its pathogenicity.

In summary, exosomes produced during animal virus infections are critical in viral pathogenesis. They exploit shared host biogenesis pathways, carry viral nucleic acids and proteins that facilitate cell-to-cell viral transmission, and actively modulate the host immune system. These features establish exosomes as promising tools for diagnosis, therapy, and vaccine innovation in veterinary virology.

4. Discussion

EVs, including exosomes, are present in all biological fluids and possess a complex cargo composition that reflects the physiological or pathological state of their cells of origin. This unique characteristic positions them as promising diagnostic biomarkers. However, the current methods for EV isolation remain suboptimal. Improving the yield and purity of exosomes continues to be a major bottleneck hindering their clinical translation (Zhang et al., 2020).

One of the major limitations in exosome research is the lack of standardized protocols for their isolation, characterization, and detection, which has led to significant inconsistencies across studies. Different laboratories frequently adopt distinct isolation methods, such as ultracentrifugation, precipitation, size-exclusion chromatography, or immunoaffinity capture, each introducing specific biases in terms of yield, purity, and the enrichment of particular vesicle subpopulations (Li et al., 2017; Zhang et al., 2018). Similarly, the use of different sets of exosomal markers (e.g., CD9, CD63, CD81, TSG101, and ALIX) without consistent application of negative controls (e.g., calnexin, ApoA1) further complicates the comparability of results (Thery et al., 2018). To address these challenges, the International Society for Extracellular Vesicles (ISEV) has issued the MISEV2018 guidelines, which outline minimal requirements for experimental design and data reporting in EV studies (Thery et al., 2018). These recommendations include detailed descriptions of sample collection, storage conditions, isolation techniques, and the use of multimodal approaches for exosome characterization, including nanoparticle tracking analysis, electron microscopy, and Western blotting for canonical markers. In addition, online platforms such as EV-TRACK encourage transparent documentation of protocols and metadata, thereby facilitating reproducibility and enabling cross-study comparisons (Consortium et al., 2017). Incorporating these standardized practices into virology-oriented exosome studies will not only enhance methodological rigor but also improve the interpretation of exosome-mediated mechanisms in viral pathogenesis, immune modulation, and therapeutic applications.

To date, most preclinical and animal studies investigating the diagnostic and therapeutic applications of EVs have focused primarily on cancer and neurological diseases. In contrast, the clinical relevance of EVs in viral infections remains relatively underexplored. Recently, attention has turned toward using EVs as targeted delivery vehicles for therapeutic agents. Despite this progress, the precise mechanisms by which EVs target and are taken up by specific recipient cells, particularly in the context of antiviral therapy, are not yet fully understood and require further investigation (Zhang et al., 2020).

Nevertheless, exosomes are now increasingly recognized as critical players in viral infections. They serve as mediators of intercellular communication and influence various aspects of viral pathogenesis. Exosomes can encapsulate and transfer viral components, including proteins, genomes, and entire particles, from infected to uninfected cells, thereby facilitating viral replication, enhancing cell-to-cell spread, and promoting immune evasion. In detail, exosomes can carry viral molecules that influence immune cell activation, inflammatory signaling, and antiviral defenses. Yet, it is crucial to acknowledge that exosome secretion is a normal physiological process. Under non-pathological conditions, exosomes contribute to immune surveillance and host defense, amplifying antiviral responses and facilitating immune activation (Li et al., 2013b). Unfortunately, many viruses have evolved mechanisms to hijack and repurpose these protective pathways to support their own persistence and dissemination. Compelling evidence now highlights the involvement of exosomes in the pathogenesis of a broad spectrum of viral infections, including HIV, hepatitis viruses, influenza, and flaviviruses, underscoring their versatile and dynamic roles across different viral families. Exosomes can enhance viral infection by suppressing autophagy, expanding viral tropism, and facilitating transmission among host cells. EVs harvested at different time points from infected cells can have altered proviral or antiviral functions due to changes in their cargo and composition over time (Rayamajhi et al., 2023). Early-released EVs can transfer viral components to prime recipient cells for infection. In contrast, EVs released later might carry different factors, potentially influencing the immune response or even contributing to viral control. One study showed that HIV-1 proteins were present in released EVs as early as 6 hours post-infection, but the EVs were not infectious. By 24 hours, there was a further increase in EV-associated HIV-1 proteins (Kim et al., 2021). Similarly, the composition of exosome cargo related to the Dengue virus changes dynamically over time, adapting to promote viral replication and disease progression. At the beginning of the infection, exosomes may carry viral RNA and proteins to assist in the virus transmission. As the infection advances, the cargo begins to shift to include microRNAs (such as miR-146, miR-155, and let-7a) that can influence immune responses in the recipient cells. Eventually, exosomes can carry microRNAs (like miR-105 and miR-590) that affect tight junction proteins, resulting in increased vascular permeability and plasma leakage commonly associated with dengue (Mishra et al., 2019). The stage of the viral replication cycle at the time of EV harvest is crucial, as it directly impacts the viral and cellular components being packaged into the EVs (Kumar et al., 2020) (Raab-Traub and Dittmer, 2017). This dual functionality of exosomes as both facilitators of viral survival and modulators of host immunity, reflects their complex and context-dependent roles in viral pathogenesis. To fully elucidate these mechanisms, the development of innovative in vivo models and advanced imaging technologies will be essential. These tools are critical for accurately tracing biogenesis, trafficking, and destination of EVs within complex biological systems such as the human body. This review has primarily focused on the multifaceted role of exosomes in viral infection and pathogenesis, illustrating how various viruses exploit exosomal pathways to promote their own replication and evade immune detection (Table 3).

Table 3.

Summary of key exosomal components associated with various viruses, their biogenesis mechanisms, roles in infection and immune modulation, and potential applications in therapeutic and diagnostic strategies.

Virus	Exosome Components	Biogenesis Mechanism	Mechanisms of Infection/Impact on Immune Response	Therapeutic/Diagnostic Potential	References
HIV	Nef, p24, gp120, TAR RNA, CCR5/CXCR4, miRNA	ESCRT-dependent, Rab GTPases	- Facilitates viral dissemination via the "Trojan exosome" hypothesis; modulates latency - Suppresses immune response via Nef; activates NF-κB and TLRs; alters cytokine secretion; downregulates CD4+ T cell activation.	Exosome-mediated delivery of HDAC inhibitors (e.g., vorinostat) to purge latency; exosome-based epigenetic repression; plasma EV biomarkers.	(Rezaie et al., 2021; Gould et al., 2003; Patters and Kumar 2018; Martin-Jaular et al., 2021; Lenassi et al., 2010; Arenaccio et al., 2014; Rahimian and He 2016; Arakelyan et al., 2017; Wu and KewalRamani 2006; Sims et al., 2017; Roth et al., 2015; Bernard et al., 2014; Chiozzini et al., 2017; Kulkarni and Prasad 2017; Sadri Nahand, Bokharaei-Salim, et al., 2020; Dias et al., 2018; Sun et al., 2016; Guo et al., 2018; Naslund et al., 2014; Chen, Li, et al., 2021; Tumne et al., 2009; Rasmussen and Lewin 2016; Pacheco et al., 2015; Chehimi, Azzoni, Farabaugh, Creer, Tomescu, Hancock, Mackiewicz, D'Alessandro, et al., 2007; Nuhn et al., 2022; Sherrill-Mix et al., 2013; Tang et al., 2018; et Shrivastava et al., 2021)
HSV-1	gB, CD63, Rab27, viral miRNAs, STING	CD63-dependent, Rab27-mediated	- Hijacks exosomes for immune evasion and viral egress - Transfers gB/HLA-DR complexes to APCs; triggers IFN responses via STING while suppressing adaptive immunity.	miRNA-loaded exosomes could inhibit replication; CD63 blockade to disrupt viral exosome pathways.	(Kalamvoki et al., 2014; Zhou et al., 2020; Grabowska et al., 2020; Temme et al., 2010; Bello-Morales and Lopez-Guerrero 2018; McLellan 2009; Muntasell et al., 2007; Li, Gu, et al., 2022; Armangue et al., 2014; Mao et al., 2023)
EBV	LMP-1, LMP-2A, EBERs, BART miRNAs	MVB budding, tetraspanins	- Transfers oncogenic LMP proteins to B and epithelial cells; promotes tumor growth and transformation: - Induces IL-10, TNF-α secretion; suppresses dendritic cell maturation; immune evasion in NPC context.	Exosomal proteins/miRNAs as biomarkers (e.g., CYPA in nasopharyngeal carcinoma); therapeutic use of Vδ2-T cell–derived exosomes for	(Zhang et al., 2015; Yang and Robbins 2011 )
SARS-CoV-2	Viral RNA, ACE2, dsRNA, cytokines	Enhanced EV formation	- Spreads viral components; triggers systemic inflammation. - Activates NF-κB/cytokine storms; mediates coagulopathy	MSC-derived exosomes for ARDS; ACE2 exosomes as decoys; biomarkers	(Gurunathan et al., 2021; Chen, Chen, et al., 2022)
ZIKV, DENV	Viral proteins (E, NS), viral RNA, microRNAs, immunomodulatory molecules	ESCRT-dependent and ESCRT-independent (autophagy-related vesicles are also involved)	- Deliver viral RNA to target cells; triggers the immune system. - Immune suppression, inflammation, and T cell exhaustion (DENV). In some cases, EVs can also deliver viral RNA to immune cells, triggering interferon responses that limit viral replication (ZIKV)	EVs as biomarkers of congenital/neurological complications (ZIKV); potential targets to prevent vascular leakage (DENV)	(Zhao et al., 2023;Kumari et al., 2025;Tiberti et al., 2025)
HBV, HCV, HAV	HBV DNA, HBsAg, HCV RNA, HAV pX, CD9/CD63/CD81	Plasma membrane fusion, ESCRT-mediated budding	- Exosomes shield viral RNA/proteins from antibodies; HAV is released in quasi-enveloped exosomes; HCV/HBV exosomes enhance cell-to-cell spread. - HBV suppresses NK cell function; HCV activates plasmacytoid DCs and induces IFN-α; HAV exosomes evade neutralization.	Exosomal HCV isolation for therapy; miR-124 delivery restores immune function; exosomes as noninvasive diagnostic markers.	(Wu and KewalRamani 2006; Sanada et al., 2017 )
HPV	E6/E7 oncoproteins, PD-L1, miR-9	ESCRT-mediated budding	- Transfers oncogenes; promotes angiogenesis/immune evasion. - Suppresses CD4+/CD8+ T cells; induces PD-L1 in fibroblasts.	Exosomal miRNAs as diagnostic markers; engineered exosomes for vaccines	(Xu et al., 2022; Ludwig et al., 2018 )
BVDV	Exosomal markers CD9, CD63, TSG101; viral RNA and proteins	Infection enhances exosome release from bovine trophoblast cells; ESCRT pathway is involved; MVB.	- Exosomes transfer viral RNA/proteins across the placenta; facilitate necrosis, apoptosis, and autophagy; enable maternal–fetal viral transmission. - Exosomal spread allows immune evasion from maternal anti-E2 antibodies; promotes placental infection and fetal disease	GW4869, an exosome inhibitor, suppressed the levels of BVDV mRNA.	(Liang et al., 2024)
PEDV	Exosomal markers ALIX, CD9, CD63; viral genomic RNA and nucleoprotein (NP)	MVB-dependent exosome release; viral RNA/NP incorporated, S and M proteins absent	- Exosomes transfer PEDV RNA/NP to permissive and non-permissive cells; are resistant to neutralizing antibodies; enhance intercellular spread. - Facilitates immune evasion from anti-PEDV antibodies; supports viral dissemination and pathogenesis	Exosomes as diagnostic markers; modulate PEDV transmission and pathogenesis	(Ding et al., 2023)
FCoV	ALIX, TSG101, CD63	ESCRT	- Exosomes deliver viral proteins and RNAs; modulate host signaling; contribute to disease progression; modulate the immune response, increase viral spread, and regulate apoptosis. - Activate transcription factors IRF and NF-κB; promote inflammatory responses; may exacerbate feline infectious peritonitis (FIP).	EVs as diagnostic and therapeutic markers	(Wijerathne et al., 2024)
AIV H5N1	Viral RNA, NP, NS1	ESCRT-independent; Rab11-mediated trafficking	- Induces proinflammatory cytokine expression; stimulates the MAPK signaling pathway. - Induce IFN-α, IFN-β, IFN-γ, IL-1β, CXCL8 and other pro-inflammatory cytokines; strong innate immune activation.	Exosomes as immunomodulatory tools and vaccine delivery platforms	(Ng et al., 2008)
PRRSV	CD63, CD81; viral RNA, GP5, N proteins	Exosomes released from the serum of infected pigs; derived from endosomes/MVB.	- Facilitates dissemination and evades immune detection. - Promote immune evasion by shielding viral components; alter miRNA cargo to modulate apoptosis and autophagy.	Exosome-based strategies in vaccine development and disease monitoring	(Wang et al., 2018c)
ASFV	Viral proteins p30 and p72, CD5, CD63, CD81, CD163	EVs released from ASFV-infected macrophages via MVB/exosome pathways	- Exosomes carry ASFV proteins and host factors; modulate recipient immune cells; contribute to vascular and immune dysregulation. - Activates IFN-α, IFN-γ, IL-6, CXCL8, affects mRNA and protein levels of NF-κB.	Exosomes as diagnostic and therapeutic markers	(Kang et al., 2025)
ALV (subgroup J most studied)	Exosomes from infected DF-1 cells (Exo-J) contain viral gag and env proteins, immunosuppressive domain (ISD) of envelope, viral RNA, and proteins;	ESCRT-dependent exosomal pathways; hijacking of host EV machinery; semen/bile-derived EVs are also involved	- Semen EVs transmit ALV-J RNA/proteins to hens and progeny. - Exosomal cargo mediates viral spread. - Dose-dependent effects: low exosome doses may activate immune cells; high doses suppress splenocyte responses; biliary exosomes promote CD4⁺/CD8⁺ T cell proliferation and restrict ALV-J replication; macrophage-derived exosomes regulate immune tolerance.	EVs as biomarkers of ALV infection and co-infection states; biliary exosomes as a potential antiviral strategy; semen EVs highlight risks for vertical transmission control.	(Wang et al., 2017; Wang et al., 2014; Ye et al., 2020; Liao et al., 2022; Zhou et al., 2018)
DHAV-1	Exosomes from infected DEFs contain full-length viral RNA, viral proteins, and occasionally intact virions	Likely ESCRT-dependent (exosomal hijacking of MVB pathway); viral exploitation of exosomal release	- Exosomes mediate productive infection in DEFs, embryos, and ducklings; exosome-mediated infection is resistant to neutralizing antibodies. - Exosomes shield DHAV-1 components from immune detection, enable immune evasion and enhance viral spread.	EVs as potential biomarkers of infection; possible therapeutic intervention to block exosome-mediated viral transmission.	(Xu et al., 2023)

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5. Conclusion

Understanding the multifaceted roles of exosomes in viral pathogenesis, immune modulation, and therapeutic response is essential for advancing our comprehension of viral diseases. Such insights will not only deepen our knowledge of virus–host interactions but also open new avenues for harnessing engineered exosomes as innovative diagnostic and prognostic tools. Ultimately, this knowledge lays the groundwork for developing novel, exosome-based therapeutic strategies to more effectively prevent, monitor, and treat viral infections.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Abbreviations

The following abbreviations are used in this manuscript:

A3G	Apolipoprotein B mRNA-editing Enzyme Catalytic Polypeptide-like
ACE2	Angiotensin-converting Enzyme 2
AE	Autoimmune encephalitis
AIDS	Acquired Immunodeficiency Syndrome
ALIX	ALG-2 Interacting Protein X
APCs	Antigen-presenting cells
ARDS	Acute Respiratory Distress Syndrome
BART	BamHI Fragment A Rightward Transcript
BL	Burkitt Lymphoma
CCR5	C-C Chemokine Receptor Type 5
CD	Cluster of Differentiation
CHB	Chronic Hepatitis B
CTLs	Cytotoxic T-lymphocytes
CXCL10	C-X-C Motif Chemokine Ligand 10
CXCR4	C-X-C Chemokine Receptor Type 4
CYPA	Cyclophilin A
DCs	Dendritic Cells
dsDNA	Double-stranded DNA
dsRNA	Double-Stranded RNA
EBERs	EBV-encoded small non-coding RNAs
EBV	Epstein-Barr Virus
EGFR	Epidermal Growth Factor Receptor
eHAV	Enveloped HAV
EMT	Epithelial-mesenchymal Transition
Env	Envelope
ERGIC	ER-Golgi Intermediate Compartment
EVs	Extracellular Vesicles
GABAB	Gamma-Aminobutyric Acid-B
gB	Glycoprotein B
GC	Gastric Carcinoma
HAV	Hepatitis A Virus
HAVCR1	HAV Cellular Receptor-1
HBsAg	Hepatitis B Surface Antigen
HBV	Hepatitis B Virus
HBx	Hepatitis B Regulatory Protein X
HCV	Hepatitis C Virus
HDACi	Histone Deacetylase Inhibitors
HDV	Hepatitis D Virus
HEV	Hepatitis E Virus
HIF1a	Hypoxia-inducible Factor-1a
HIV	Human Immunodeficiency Virus
HL	Hodgkin Lymphoma
HLA-DR	Human Leukocyte Antigen – DR Isotype
HNSCC	Head and Neck Squamous Cell Carcinoma
HPV	Human Papillomavirus
HRS	Hepatocyte Growth Factor-Regulated Tyrosine Kinase Substrate
HSE	Herpes Simplex Encephalitis
HSV-1	Herpes Simplex Virus Type 1
IDO	Indoleamine 2,3-dioxygenase
IFN	Interferon
IKK	IkB Kinase
ILVs	Intraluminal Vesicles
KSHV	Kaposi's sarcoma virus
La	Lupus antigen
LMP-1	Latent membrane protein 1
LMP-2A	Latent membrane protein 2A
MHC	Major Histocompatibility Complex
miRNA	microRNA
MRI	Magnetic Resonance Imaging
MSC	Mesenchymal Stem Cell
MVBs	Multivesicular bodies
Nef	Negative Regulatory Factor
NF-κB	Nuclear Factor Kappa-light-chain-enhancer of activated B Cells
NHL	Non-Hodgkin Lymphoma
NK	Natural Killer
NMDA	N-Methyl-D-Aspartate
NPC	Nasopharyngeal Carcinoma
NPC1	Niemann–Pick C
NSP	Non-structural proteins
OSCC	Oral Squamous Cell Carcinoma
PC	Phosphatidylcholine
pDC	Plasmacytoid Dendritic Cell
PS	Phosphatidylserine
PTMs	Post-translational modifications
RER	Rough Endoplasmic Reticulum
RIG-I	Retinoic Acid-Inducible Gene I
RSV	Respiratory Syncytial Virus
TAR	Transactivation Response
TGN	Trans-Golgi Network
Th	T helper
TLRs	Toll-Like Receptors
TMPRSS2	Transmembrane Protease, Serine 2
TNF-α	Tumor necrosis Factor
TSG101	Tumor Susceptibility 101
Vps4	Vacuolar Protein Sorting-Associated Protein 4

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CRediT authorship contribution statement

Roberta Della Marca: Writing – original draft, Investigation. Rosa Giugliano: Writing – original draft, Visualization. Carla Zannella: Writing – review & editing, Supervision. Marina Acunzo: Visualization. Preetu Parimal: Methodology. Avinash Mali: Writing – original draft. Annalisa Chianese: Writing – original draft, Methodology. Valentina Iovane: Writing – review & editing. Massimiliano Galdiero: Writing – review & editing, Conceptualization. Anna De Filippis: Writing – review & editing, Resources, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Footnotes

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.virusres.2025.199644.

Contributor Information

Roberta Della Marca, Email: roberta.dellamarca@unicampania.it.

Rosa Giugliano, Email: rosa.giugliano@unicampania.it.

Carla Zannella, Email: carla.zannella@unicampania.it.

Marina Acunzo, Email: marina.acunzo@unicampania.it.

Preetu Parimal, Email: preetu.parimal@unicampania.it.

Avinash Mali, Email: avinash.mali@uj.edu.pl.

Annalisa Chianese, Email: annalisa.chianese@unicampania.it.

Valentina Iovane, Email: valentina.iovane@unina.it.

Massimiliano Galdiero, Email: massimiliano.galdiero@unicampania.it.

Anna De Filippis, Email: anna.defilippis@unicampania.it.

Appendix. Supplementary materials

mmc1.docx^{(19.9KB, docx)}

Data availability

Data will be made available on request.

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Supplementary Materials

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Data Availability Statement

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PERMALINK

Role of exosomes in viral infections: a narrative review

Roberta Della Marca

Rosa Giugliano

Carla Zannella

Marina Acunzo

Preetu Parimal

Avinash Mali

Annalisa Chianese

Valentina Iovane

Massimiliano Galdiero

Anna De Filippis

Highlights

Abstract

Graphical abstract

1. Introduction

1.1. Advantages and methodological challenges in exosomes research

Table 1.

1.2. Exosomes main characteristics

Fig. 1.

Fig. 2.

Table 2.

2. Methodology

Fig. 3.

3. Role of exosomes in human and animal infectious diseases

3.1. Role of exosomes in HIV infection

Fig. 4.

3.1.1. Proviral effects of EVs in HIV infection

3.1.2. Antiviral effects of EVs in HIV infection

3.1.3. EVs' therapeutic application in HIV infection

3.2. Role of exosomes in HSV infection

3.2.1. EVs roles in HSV replication and egress

3.2.2. EVs impair the host immune response in HSV infection

Fig. 5.

3.2.3. EVs deliver antiviral molecules in HSV infection

3.2.4. EVs microRNA conflictual role in HSV infection

3.3. Role of exosomes in Epstein-Barr virus (EBV) infection

3.3.1. EVs in EBV-associated cancer progression and immune modulation

Fig. 6.

3.3.2. EVs in EBV-associated cancer therapies

3.4. Role of exosomes in Coronaviruses (CoV) infection

Fig. 7.

3.4.1. EVs influence immune response during SARS-CoV-2 infection

3.4.2. EVs' therapeutic application in SARS-COV-2 infection

3.5. Role of exosomes in Flavivirus infection

3.5.1. EVs in human host: proviral and antiviral role

3.5.2. EVs in mosquito vector: proviral and antiviral role

3.6. Role of exosomes in Hepatitis virus infection

Fig. 8.

3.6.1. EVs role in Hepatitis egress

3.6.2. EVs participate in Hepatitis infection and immune evasion

3.6.3. EVs enhance immune signaling against hepatitis

3.6.4. EVs carry antiviral molecules against hepatitis

3.7. Role of exosomes in Human papillomavirus (HPV) infection and cancer

3.7.1. EVs immune modulation in HPV infection and tumor progression

Fig. 9.

3.7.2. EVs therapeutic application in HPV infection

3.8. Role of exosomes in animal viral infection

4. Discussion

Table 3.

5. Conclusion

Funding

Institutional Review Board Statement

Informed Consent Statement

Abbreviations

CRediT authorship contribution statement

Declaration of competing interest

Footnotes

Contributor Information

Appendix. Supplementary materials

Data availability

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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