Extracellular Vesicles in COVID-19: Mechanistic insights and emerging therapeutic strategies

Abstract

The COVID-19 pandemic has profoundly impacted global health, driven in part by the high mutation rate of SARS-CoV-2, which has resulted in the emergence of variants with enhanced transmissibility, virulence, and immune evasion capabilities. This evolving threat highlights the urgent need for innovative therapeutic strategies, as current treatments have shown limited efficacy. In this context, Extracellular Vesicles (EVs) present a promising alternative. EVs play a crucial role in intercellular communication and offer advantages due to their biocompatibility and mechanisms of cellular entry as viruses, making them an important tool against SARS-CoV-2. One of the principal immune evasion strategies employed by SARS-CoV-2 involves the release of EVs capable of transporting viral antigens. Numerous studies have suggested the role of exosomes and microvesicles as carriers of viral components, indicating that EVs can be targets in the progression of infection. Exosomes derived from infected cells could function as biomarkers and as potential drug delivery vehicles. Furthermore, EVs play a regulatory role in immune responses, facilitating cytokine production and antigen presentation. This review aims to elucidate the molecular mechanisms underlying the involvement of EVs in SARS-CoV-2 infection, examine their implications for biomarker development and explore their potential therapeutic applications in COVID-19.

Key words
COVID-19; extracellular vesicles; SARS-CoV-2; therapeutic target; vaccines

INTRODUCTION

The term “Extracellular Vesicles” (EVs) was introduced in 2011 as a collective designation for cell-derived particles enclosed by a lipid bilayer (György et al. 2011). EVs exhibit significant biophysical, biochemical, and functional heterogeneity (Théry et al. 2002). These vesicles function as natural mediators of intercellular communication in living organism, with growing interest in various biotechnological fields. Their relevance is particularly pronounced in medicine, where they play crucial roles in the diagnosis and treatment of infectious diseases such as COVID-19 (Nair et al. 2023, D’Avila et al. 2024).

The high mortality rate associated with COVID-19 predominantly affects older populations and individuals with pre-existing conditions, including cardiovascular diseases, chronic respiratory conditions, hypertension, and cancer (Wu & McGoogan 2020). SARS-CoV-2, the causative agent of COVID-19, is described as a highly transmissible virus, spreading at alarming rates globally. Like all viruses, SARS-CoV-2 is an obligate intracellular parasite, reliant on host metabolic pathways for its biosynthetic needs. The pathogenesis of COVID-19 is closely linked to the complex interplay between SARS-CoV-2 and host cells (Proal & VanElzakker 2021). Understanding these cellular and molecular interactions is critical for elucidating the mechanisms of disease progression.

SARS-CoV-2 host cells infection and its subsequente replication, induces a cascade of host responses which results in tissue damage, cytokine storms, and release of EVs. These vesicles carry a variety of biomolecules, including proteins, enzymes, lipids, and nucleic acids (Xia et al. 2023). Among these molecules, the presence of angiotensin-converting enzyme 2 (ACE-2) is of particular interest, as it may either facilitate or hinder viral entry and colonization (Cocozza et al. 2020, El-Shennawy et al. 2022, Berry et al. 2022).

The development of accurate diagnostic tools, effective therapeutics, and improved vaccines is paramount for addressing diseases caused by intracellular pathogens. Moreover, identifying key signaling pathways within host cells that are critical for viral replication may uncover novel therapeutic targets. In this context, EVs represent promising targets for therapeutic intervention in the treatment of COVID-19 and other coronavirus-related infections.

In this review, we summarize current knowledge on the role of EVs in modulating immune responses, evasion mechanisms, and inflammatory pathways, and highlight advancements in potential therapeutic applications for COVID-19.

This review was conducted through a systematic analysis of scientific literature, focusing on articles published between 2000 and 2024, retrieved from databases including PubMed, Scielo, and CAPES Journals. The search terms employed included “Extracellular Vesicles,” “Extracellular Vesicles and COVID-19,” “Extracellular Vesicles and Vaccine,” “SARS-CoV-2 and Extracellular Vesicles,” “Vaccine and COVID-19,” and “SARS-CoV-2 and Structure.” A total of 117 articles were selected based on experimental design, randomized or non-randomized clinical trials, and observational studies. Correspondences, editorial comments, conference abstracts, and article commentaries were excluded from this analysis.

Origin, Classification and Composition of EVs

Extracellular vesicles (EVs) are secreted by all cellular organisms, including bacteria and archaea, demonstrating that the production of these nanostructures is a conserved feature across all three domains of life: Archaea, Bacteria, and Eukaryota (Toyofuku et al. 2019). EVs are biological nanostructures essential for intercellular communication, functioning as carriers of diverse biomolecules such as proteins, lipids, growth factors, mRNAs, and non-coding RNAs (ncRNAs), including microRNAs (miRNAs) (Théry et al. 2018). These vesicles mediate signaling between different cell types, facilitating intercellular communication (van Niel et al. 2018, Pathan et al. 2019). As such, EVs are essential to maintaining homeostasis and play significant roles in the progression of pathological processes (Toyofuku et al. 2019, van Niel et al. 2018, Almeida et al. 2024).

EVs are classified into distinct subpopulations, including large extracellular vesicles (lEVs) and small extracellular vesicles (sEVs), based on their origin, size, and content (Cocucci & Meldolesi 2015). Small EVs, commonly referred to as exosomes, are released following the fusion of multivesicular bodies (MVBs) containing intraluminal vesicles (ILVs) with the plasma membrane. Exosomes are formed during the late stages of endosome maturation when MVBs accumulate ILVs, which are subsequently released into the extracellular space. These vesicles range from 20 to 140 nm in size and may express surface proteins such as ALG-2-interacting protein X (ALIX) and tetraspanins (CD63, CD9, CD81, and TSG101), which facilitate their role in intercellular communication (Fujii et al. 2007, Colombo et al. 2014, Ha et al. 2016). Proteins involved in exosome biogenesis, such as the Endosomal Sorting Complex Required for Transport (ESCRT), vacuolar ATPase, and vacuolar protein sorting-associated protein 4A (VPS4), are crucial for this process (Théry et al. 2002, Kumar et al. 2014). Additionally, recent studies have suggested the involvement of other endomembranes, such as the endoplasmic reticulum and nuclear envelope, in exosome formation (Barman et al. 2022).

Furthermore, ceramide synthesis within the plasma membrane and endosomes has been shown to regulate EV biogenesis (Hurley 2015). In this study, it was demonstrated that inhibiting neutral sphingomyelinase (nSMase) in animal and human cells reduces exosome release, while increasing the release of microvesicles from the plasma membrane.

Large vesicles are generated form via the outward budding of the plasma membrane followed by fission. These vesicles are often referred to as microvesicles, ectosomes, microparticles, or exovesicles in the literature, typically range from 0.5 to 1,000 nm in size (Théry et al. 2002). Although lEVs share functional similarities with exosomes, they differ in their origin, arising directly from the plasma membrane. Specific markers, including phosphatidylserine, Rac GTPase-activating protein-1 (RACGAP-1), and kinesin family member proteins (KIF23), distinguish these vesicles (Skog et al. 2008, Arya et al. 2022, Hernández et al. 2023). However, specific molecular markers to their distinct biosynthetic routes remain elusive. Another class of vesicles, apoptotic bodies, ranges from 50 to 5,000 nm in size and has the primary function of enclosing and protecting cellular components during apoptosis. These vesicles are characterized by markers such as DNA, phosphatidylserine, and gp96 protein (van der Pol et al. 2012, Jeppesen et al. 2019).

A study by Maas et al. (2017) discussed the regulatory mechanisms governing EV budding from the plasma membrane, suggesting that EV biogenesis is dynamic, and the exocytosis pathways adapts to the specific needs of the cell (Trajkovic et al. 2008). The fate of EVs, once formed, is shaped by various physiological or pathological conditions of the producing cells (Menck et al. 2017, Li et al. 2021). Aspects such as vesicles size, surface composition (lipids, glycans, and proteins), pH, temperature, and oxidative or hypoxic environments critically influence their interactions with target cells (Liu & Wang 2023, Buzas 2022).

Over the past 40 years, increasing research production has explored the role of EVs in the pathogenesis of cancer, neurodegenerative diseases, and infections, including COVID-19 (Jafari et al. 2019, Almeida et al. 2024, Hill 2019, Chow & Morphew 2023, Gould et al. 2003).

Different studies have demonstrated the ability of EVs to deliver viral genomes to host cells in vitro, with examples from Herpes Simplex Virus 1, Hepatitis C Virus (HCV), Hepatitis A Virus (HAV), Human Herpesvirus 6 (HHV-6), and SARS-CoV-2 (Kumar et al. 2020, Raab-Traub & Dittmer 2017, Dias et al. 2020). Due to their structural and functional similarities to viruses, EVs have attracted significant attention as potential mediators in viral spread. These similarities, including their small size, shared biogenesis mechanisms, and strategies for cell entry, highlight their potential role in facilitating viral transmission (Gould et al. 2003). For example, both viruses and EVs rely on the endocytic pathway to enter host cells and exit through “budding” at the cell membrane (Pocsfalvi et al. 2020).

The “Exosomal Trojan Horse Hypothesis,” first proposed by Gould et al. (2003) and later refined by Izquierdo-Useros et al. (2010), builds upon these parallels. It suggests that EVs, including exosomes, can incorporate pathogen-derived molecules, effectively transforming them into vectors for viral transmission. This hypothesis posits that retroviruses exploit the natural biogenetic pathways of exosomes to produce infectious particles, utilizing shared protein-targeting and biogenetic mechanisms to hijack preexisting exosome uptake pathways. As a result, viruses gain access to receptor-independent and envelope protein-independent routes of infection, enhancing their ability to evade immune responses, spread more effectively, and increase infectivity.

In the context of COVID-19, this hypothesis holds particular significance. By suggesting that SARS-CoV-2 could utilize EVs to facilitate its transmission and pathogenesis, the Trojan Horse hypothesis opens avenues for understanding the virus’s mechanisms of immune evasion and infectivity. This underscores the need for further research into EV-mediated viral transmission, which could provide novel insights into therapeutic strategies to combat the spread and severity of SARS-CoV-2 (Figure 1).

Figure 1
Extracellular vesicles as Trojan Horses in SARS-CoV-2 infection. After infecting a host cell, SARS-CoV-2 induces the production of extracellular vesicles that act as Trojan horses, carrying viral particles, genetic material, and proteins. These vesicles are released into the extracellular environment, where they interact with uninfected cells, triggering inflammatory responses and the release of cytokines.

SARS-CoV-2: Infection Mechanisms and Inflammatory Responses in COVID-19

SARS-CoV-2, like other coronaviruses, is an enveloped (+RNA) virus that encodes instructions for the expression of key proteins within host cells (V’kovski et al. 2021). The membrane (M) protein, the most abundant structural protein, plays a central role in viral assembly. The nucleocapsid (N) protein binds to the viral RNA genome, participating in both viral RNA synthesis and the regulation of host cell processes. The envelope (E) protein is critical for viral assembly, budding, and pathogenesis, and it also influences virus-host cell interactions. The spike (S) protein facilitates viral entry into host cells by binding to the ACE-2 receptor, enabling attachment and fusion with host cells (Malik 2020). Additionally, the S protein is a key target for neutralizing antibodies and vaccine development (Figure 2). Non-structural proteins, including RNA-dependent RNA polymerase (RdRp) and helicase, form the replication-transcription complex (RTC), essential for viral replication and transcription (Chen et al. 2022).

Figure 2
Structure of SARS-CoV-2 and mechanisms of interaction with target proteins in the host cell. a) Main components of the viral particle; b) Molecules involved in the interaction/infection of SARS-CoV-2 with the host cell - The TMPRSS2 protein aids in viral entry by cleaving the S protein and/or the S protein interacts with the ACE-2 receptor, inducing the viruses enters via endocytosis or membrane fusion in regions which are rich in ceramide. Once inside the host cell, the viral RNA is translated into proteins essential for the viral replication cycle.

Viruses are obligate intracellular parasites that require the host cell machinery for replication (Hazal & Gerlier 2003, Takahashi & Suzuki 2011). Once SARS-CoV-2 reaches the bronchi, having passed through the oral and respiratory mucosa, the spike (S) protein interacts with the ACE2 receptor, which is highly expressed in bronchial epithelial cells, particularly in type II pneumocytes (Fung & Liu 2019, Shi et al. 2014) (Figure 2B). The TMPRSS2 protein assists viral entry by cleaving the S protein. Inside the host cell, viral RNA is released and subsequently translated into various viral proteins (Figure 2B). Ribosomes associated with the host cell’s endoplasmic reticulum synthesize the non-structural proteins (NSPs), which contribute to the assembly of new viral particles. These newly formed viruses are released from the host cell through exocytosis, completing the viral replication cycle (Santos-Lopez et al. 2021, Yadav et al. 2021).

Viruses interact with multiple intracellular structures and reprogram cellular lipid metabolism to favor their replication (Syed et al. 2010, Zhang et al. 2017). They activate transcription factors and enzymes that promote lipid biosynthesis and accumulation, leading to the formation of lipid droplets (LDs) (Qu et al. 2023, Villareal et al. 2015). Increasing evidence highlights LDs as critical hubs in the viral replication cycle and in the pathogenesis of different diseases, suggesting the potential of these organelles as therapeutic targets (Lyn et al. 2013, Filipe & McLauchlan 2015, Dias et al. 2020, Barbosa-Lima et al. 2020).

For many years, LDs were regarded as simple cytoplasmic lipid inclusions. However, recent studies have revealed them to be dynamic organelles involved in lipid metabolism, energy homeostasis, protein storage, cellular signaling, and inflammatory responses (Welte & Gould 2017, Olzmann & Carvalho 2019). Several studies have demonstrated that viral molecules interact with key components related to LD biogenesis and structure, emphasizing the importance of these organelles for viral replication (Lyn et al. 2013, Samsa et al. 2009). RNA viruses, including members of the Flaviviridae family, as well as rotavirus, reovirus, and coronaviruses, use LDs as platforms for replication (Cheung et al. 2010, Coffey et al. 2006, Ripon et al. 2021).

SARS-CoV-2 infection also modulates the expression of several inflammatory mediators, such as interleukins (IL-1, IL-6, IL-10, TNF-α), chemokines (IL-8, CXCL10), and eicosanoids (prostaglandins, thromboxanes, leukotrienes), all of which play pivotal roles in immune response and inflammation (Ye et al. 2020, Ramasamy & Subbian 2021, Liu et al. 2024). Additionally, the regulation of transcription factors like Sterol Regulatory Element-Binding Protein (SREBP) and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) directly impacts the release of pro-inflammatory cytokines, such as IL-1 and IL-18, and may also prevent inflammasome activation (Soares et al. 2023, Geng & Duo 2023).

Lipid metabolic reprogramming and LD biogenesis during viral infection have paved the way for new therapeutic strategies against COVID-19 (Qu et al. 2023). Soares et al. (2023) demonstrated that both SREBP and PPARγ, which play key roles in LD biogenesis, are modulated during infection. SREBP regulates the expression of metabolic enzymes involved in fatty acid and cholesterol synthesis, essential for LD formation (Yuan et al. 2021). PPARγ regulates the expression of genes related to lipid synthesis and uptake, contributing to LD formation (Soltani-Zangbar et al. 2022). Different studies suggest that the activation of SREBP and PPARγ during SARS-CoV-2 infection may amplify the immune response and contribute to COVID-19 pathogenesis by regulating inflammatory mediator expression.

By targeting LDs in host cells, the main reservoirs of neutral lipids, SARS-CoV-2 secures crucial energy substrates to fuel its replication cycles (Dias et al. 2020). Viral replication is further enhanced by exploiting the host cell’s secretory machinery (Soltani-Zangbar et al. 2022). SARS-CoV-2 enters the endocytic pathway and uses exocytic lysosomes for exiting the infected cell (Ghosh et al. 2021). When viral particles enter lysosomes via late endosomes or multivesicular bodies (MVBs), it is possible that viral components and exosomes interact before exocytosis and release of these organelles’ contents (Wei et al. 2020, Martin et al. 2024). This sophisticated viral strategy may include the release of exosomes to evade the immune system, potentially promoting viral replication and disease progression (Wurdinger et al. 2012).

Role of EVs during SARS-CoV-2 infection

There is a duality in the roles that EVs play in viral infection and propagation mechanisms. Both EVs and viruses share similar sizes, typically ranging from 30–200 nm for EVs and up to 300 nm for enveloped viruses. They also exhibit structural overlap, with lipid bilayer membranes enriched in proteins and lipids critical for their functions (Martin et al. 2024). Furthermore, EVs and viruses utilize convergent biogenesis routes, such as the endosomal sorting complex required for transport (ESCRT) machinery and share uptake pathways like clathrin-mediated endocytosis and macropinocytosis, enabling them to interact with target cells effectively (van Niel et al. 2018).

In addition to these similarities, corroborating Trojan horse hypothesis during viral infections EVs can carry viral components, including proteins and genetic material as RNAs or DNA fragments, facilitating intercellular communication and potentially aiding in the spread of the infection (Rey-Cadilhac et al. 2023).

Furthermore, EVs are not limited to transport in biological fluids, they can also accumulate and operate within solid tissues. Within these solid tissues, EVs efficiently deliver their cargo such as proteins, miRNAs, mRNAs, and lncRNAs to nearby or distant cells. This delivery mechanism enables EVs to reprogram the recipient cells, altering their fate, functionality, and morphology, which may lead to physiological adaptations or pathological effects (Maas et al. 2017, Statello et al. 2018).

At the same time, EVs may support host defense mechanisms by delivering antiviral molecules or signaling components that activate immune responses. However, their ability to shield viral materials within a membrane-bound vesicle can also provide viruses with an immune evasion strategy, further highlighting the dual role of EVs in the context of infection (Schneider & Simons 2013). This multifaceted interplay between EVs and viruses underscores their significance as both mediators of disease and potential therapeutic targets.

A recent study demonstrated that EVs derived from HEK293T cells enriched with ACE2 can enhance SARS-CoV-2 infection in a dose-dependent manner, likely due to the efficient uptake of EVs by host cells (Zhu et al. 2021). The packaging of viral particles in exosomes may protect the virus from neutralization by antibodies, enabling it to infect cells that lack viral receptors and would otherwise be immune to the pathogen (Alzahraani et al. 2021, Horn & MacLean 2021).

Additional evidence has indicated that EVs derived from human nasal epithelial mucus (mu-EVs) enhance the infectivity of SARS-CoV-2 (Rubio-Casillas et al. 2022, Choi et al. 2022). The authors demonstrated that after SARS-CoV-2 binds to ACE2 and TMPRSS2 in mu-EVs, cleavage of the S1/S2 domain occurs, leaving the spike protein in an ‘open’ conformational state, priming it for fusion (Weisblum et al. 2020, Essalmani et al. 2022). This process may primarily depend on TMPRSS2 protease activation; however, no TMPRSS2 activation was detected in the study by Tey & Yam (2022). Furthermore, in vitro studies suggest that EVs from different cellular origins exert varying effects on SARS-CoV-2, depending on their surface protein composition. However, further studies are needed to fully elucidate how these processes operate in vivo (Kwon et al. 2020).

Supporting these findings, Verta et al. (2022) demonstrated that EVs containing S1 or S2 proteins are more readily absorbed by ACE2-expressing cells. Moreover, EVs engineered with ACE2 can neutralize SARS-CoV-2 by acting as nano-decoys that competitively bind to the viral spike protein, thereby inhibiting viral entry and offering a potential preventive strategy against viral spread (El Andaloussi et al. 2013) (Figure 2). However, the use of exogenous EVs as nano-decoys for SARS-CoV-2 remains to be further explored and clarified.

Although some studies have detected SARS-CoV-2 RNA in plasma EVs from the early stages of infection, more research is needed to evaluate the presence of genomic and subgenomic SARS-CoV-2 RNA in circulating EVs (Popowski et al. 2022). A comprehensive understanding of the molecular mechanisms involved in the interaction and entry of EVs and viruses is essential for elucidating how viruses exploit and manipulate EV machinery to their advantage (Figure 3).

Figure 3
Role of EVs during SARS-CoV-2 infection. The similarities in the biogenesis of EVs and in SARS-CoV-2 infection lead to the packaging and release of viral proteins in EVs. The Spike protein expressed in EVs can act as a nano-decoy to neutralize antibodies by activating the immune response. The presence of ACE2 in EVs represents decoys for the virus. EVs contribute to the escape mechanism from leukocytes and neutralizing antibodies, as well as provide a niche for viral uptake. Damage-Associated Molecular Patterns (DAMPs) released by apoptotic cells activate immune system cells and release inflammatory mediators, which under adverse conditions lead to a cytokine storm. The EVs released represent key mediators of inflammation and molecular cargo transfer between cells, acting both as decoy for the virus and for neutralizing antibodies.

Exploring Extracellular Vesicles as Therapeutic Targets for COVID-19

Currently, EVs are being considered as potential therapies for various clinical conditions, particularly those with significant immunological or inflammatory components. Their biocompatibility, low immunogenicity, and cellular entry mechanisms, which closely resemble those of viruses, make them advantageous over synthetic nanoparticles (Kim & Thapa 2023). These properties position EVs as promising candidates for applications in vaccines and drug delivery systems (Figure 3).

In the ongoing fight against COVID-19, a promising strategy involves utilizing (EVs) as platforms for vaccine delivery, given their ability to efficiently transport viral antigens (Brezgin et al. 2023). EV-based vaccines offer several advantages, including enhanced stability and prolonged antigen presentation, which can result in more targeted and effective activation of the immune system (Wang et al. 2022).

The development of EV-based vaccines requires several key steps. First, EVs must be isolated from secretory cells, such as dendritic or tumor cells, using techniques like ultracentrifugation to ensure effective separation. Next, the desired antigens, such as viral proteins or peptides, are loaded into the EVs. These antigens can either be pre-loaded into the cells before EV isolation or added externally to already isolated EVs (Matsuzaka & Yashiro 2023). EVs can also be engineered to enhance their efficacy by incorporating membrane proteins or nucleic acids, which helps direct their activity (Zhang et al. 2023). This enables a more precise immune response, potentially reducing the risk of adverse effects commonly associated with traditional vaccine delivery methods. Additionally, EVs’ ability to disseminate throughout the body is a significant advantage, as they can transport materials of interest to hard-to-reach areas, such as the central nervous system, by crossing the blood-brain barrier (Hernández-Díazcouder et al. 2023).

Moreover, EV-based vaccines are gaining attention for their ability to display specific viral antigens, inducing more efficient immune responses (Xie et al. 2021). While vaccines are the most effective form of prevention, they still face challenges in providing protection against new mutant strains, such as the highly transmissible Omicron variant. Furthermore, the potential of EVs to act as nano-decoys in the defense against SARS-CoV-2 has been demonstrated in various in vivo animal experiments. In this context, in addition to their roles as therapeutic tools and drug delivery vehicles, EVs can be explored as biomarkers for disease monitoring and treatment (Matsumoto et al. 2018, Garcia-Beltran et al. 2022).

EVs can be tailored to target specific cell populations, minimizing adverse effects. By modulating the composition and contents of EVs, it is possible to optimize their immunomodulatory properties, thereby enhancing their ability to elicit robust and durable host responses against the virus (Jia et al. 2022). Thus, the development of EV-based vaccines against COVID-19 could represent a paradigm shift in vaccination strategies, offering a versatile platform with the potential to overcome many of the challenges associated with traditional vaccine formulations (Motalebbnezhad et al. 2023, Gowen et al. 2020).

Nevertheless, despite promising preclinical data, several challenges must be overcome before EV-based vaccines can transition to clinical use. These challenges include improving purification processes, identifying subpopulations with therapeutic potential, scaling up production, optimizing dosage, and refining methods of administration. Additionally, it is crucial to ensure the safety of EVs in terms of toxicity, immune response, pharmacodynamics, and to fully elucidate their mechanisms of action in vivo (Yan et al. 2021, Krishnan et al. 2022, Moradinasab et al. 2021).

In this context, Table I provides an overview of current studies using EVs derived from mesenchymal stem cells (MSC-EVs). MSC-EVs show high clinical potential due to their unique intercellular communication capabilities, tissue regeneration properties, and enhanced safety compared to EVs from other cellular origins. Furthermore, MSC-EVs have been investigated for their potential to mitigate the cytokine storm, a severe complication associated with COVID-19 (Fang et al. 2023).

Table I
Clinical studies related to the use of EVs in patients with COVID-19. The studies are listed with their respective Titles, NCT Number, Status, Comorbidity, Intervention, Study Type, and Start Date. The data was obtained from ClinicalTrials.gov, providing an overview of ongoing research on the therapeutic potential of EVs in COVID-19, using the search terms “COVID-19” and “Extracellular vesicles”.

Titles	NCT Number	STATUS	Comorbidity	Intervention	Study Type	Start Date
Extracellular Vesicle Infusion Treatment for COVID-19 Associated ARDS	NCT04493242	Complete	COVID-19 ARDS	Biological: ExoFlo Other: Intravenous Normal Saline	Intervention	24/09/2020
A Clinical Study on Safety and Effectiveness of Mesenchymal Stem Cell Exosomes for the Treatment of COVID-19.	NCT05787288	Recruiting	COVID-19 Pneumonia	Biological: Mesenchymal Stem Cell Extracellular Vesicles	Intervention	23/01/2023
Expanded Access for Use of bmMSC-Derived Extracellular Vesicles in Patients With COVID-19 Associated ARDS	NCT04657458	Available	COVID-19 ARDS (Acute Respiratory Distress Syndrome) Hypoxia Cytokine Storm	Biological: ExoFlo	Expanded Access	08/12/2020
ExoFlo™ Infusion for Post-Acute COVID-19 and Chronic Post-COVID-19 Syndrome	NCT05116761	Not yet recruiting	COVID-19 Post-Viral Syndrome Dyspnea	Biological: Bone Marrow-Derived Mesenchymal Stem Cell Extracellular Vesicles Other: Saline Solution	Intervention	11/11/2021
Zofin to Treat COVID-19 Long Haulers	NCT05228899	Complete	COVID-19	Drug: Zofin Other: Placebo	Intervention	14/04/2022
Safety and Efficacy of Umbilical Cord Mesenchymal Stem Cell Exosomes in Treating Chronic Cough After COVID-19	NCT05808400	Recruiting	Persistent Post-COVID-19 Syndrome	Biological: Mesenchymal Stem Cell-Derived Exosomes	Intervention	15/02/2023
Study of the Vascular Compartment and Hypercoagulability During Coronavirus Infection COVID-19	NCT04367662	Complete	COVID-19	Procedure: Blood Collection	Intervention	09/04/2020
Cognitive Impairment and Fatigue After Mild to Moderate COVID-19	NCT06042530	Recruiting	Post-COVID-19 Condition Cognitive Impairment Mental Fatigue	Diagnostic Test: Neuropsychological Assessment; Optometric Investigation; Magnetic Resonance Imaging; Immunological Biomarkers	Observational	01/04/2021

Although EVs demonstrate great potential, research in this field is still in its early stages, requiring significant investments and more robust results to drive progress. Additionally, exosome-based therapies, such as ExoFlo, are being investigated and warrant further exploration for their potential applications. ExoFlo involves the use of exosomes products derived from mesenchymal stem cells from bone tissue and is currently being considered as a treatment for severe COVID-19 (Murugan & Rangasamy 2022, Sengupta et al. 2020). However, further studies are necessary to fully establish its efficacy in preventing disease progression.

CONCLUSIONS

Intracellular pathogens, such as coronaviruses, which possess a high capacity for dissemination and mutation, present ongoing challenges that require continuous scientific investigation and the exploration of innovative vaccine technologies. Among these, extracellular vesicles (EVs) have emerged as a promising platform with the potential to reshape vaccination strategies. EVs offer unique advantages due to their natural ability to facilitate intercellular communication, their biocompatibility, and their capacity to carry and present antigens effectively (Figure 4). These properties bring renewed optimism in the fight against highly adaptive and transmissible pathogens like SARS-CoV-2.

Figure 4
Exosomes as Novel Platforms for Therapeutic Drug Delivery. Exosomes can be released by cells: a) carry new viral particles, which contributes to viral dissemination; b) transport proteins and genetic material; c) can be utilized for drug delivery by isolating and modifying them to serve as carriers for pharmaceuticals; d) transport biological molecules such as mRNA, siRNA, and antigens, with the goal of enhancing vaccine efficacy.

While current research into EV-based vaccines is still in its early stages, the potential applications are broad, ranging from the delivery of viral antigens to the modulation of immune responses in a more targeted and efficient manner. As we continue to face the emergence of new viral strains, such as the Omicron variant of SARS-CoV-2, which pose challenges for traditional vaccines, EVs represent a flexible and adaptable platform that could meet these evolving threats.

The transformative potential of EV-based vaccines lies in their ability to address some of the limitations associated with conventional vaccine technologies, such as stability, scalability, and delivery to hard-to-reach tissues, including the central nervous system. Additionally, EVs have shown potential not only as antigen carriers but also as therapeutic agents capable of mitigating complications like the cytokine storm seen in severe cases of COVID-19. These characteristics, opens new avenues for their application beyond preventative vaccines, extending to therapeutic interventions and disease monitoring.

To fully realize the promise of EV-based vaccines, substantial research and investment are needed to optimize production methods, improve purification techniques, and refine the targeting of specific cell populations. Furthermore, understanding the in vivo mechanisms of EVs and their interactions with the immune system remains crucial for ensuring both safety and efficacy. By capitalizing on the unique properties of EVs, we can potentially develop more effective and safer immunization strategies that not only protect against COVID-19 but also provide a robust defense against a wide range of viral pathogens. In conclusion, the continued exploration and development of EV-based technologies could revolutionize how we approach vaccines, offering a versatile and dynamic tool in the ongoing battle against infectious diseases. With further research, investment, and collaboration, EV-based vaccines may hold the key to overcoming some of the most pressing challenges in global health.

Acknowledgements

The authors would like to thank the Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG, Brasil), the Fundação de Apoio à Pesquisa do Distrito Federal (FAPDF, Brasil) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico do Brasil (CNPq, Brasil).

References

• ALMEIDA PP, MORAES JA, BARJAFIDALGO TC & RENOVATO-MARTINS M. 2024. Extracellular vesicles as modulators of monocyte and macrophage function in tumors. An Acad Bras Cienc 96: e20231212. DOI 10.1590/0001-3765202420231212.
• ALZAHRAANI FA ET AL. 2021. Untargeted metabolic profiling of extracellular vesicles of SARS-CoV-2-infected patients shows presence of potent anti-inflammatory metabolites. Int J Mol Sci 22: 10467.
• ARYA SB, CHEN S, JORDAN-JAVED F & PARENT CA. 2022. Ceramide-rich microdomains facilitate nuclear envelope budding for non-conventional exosome formation. Nat Cell Biol 24: 1019-1028.
• BARBOSA-LIMA G, HOTTZ ED, DE ASSIS EF, LIECHOCKI S, SOUZA TML, ZIMMERMAN GA, BOZZA FA & BOZZA PT. 2020. Dengue virus-activated platelets modulate monocyte immunometabolic response through lipid droplet biogenesis and cytokine signaling. J Leukoc Biol 108(4): 1293-1306.
• BARMAN B, DAWSON TR & WEAVER AM. 2022. ER membrane contact sites: key platforms for biogenesis of RNA-containing extracellular vesicles. Contact 5: 251525642211214.
• BERRY F ET AL. 2022. Proviral role of human respiratory epithelial cell-derived small extracellular vesicles in SARS-CoV-2 infection. J Extracell Vesicles 11: e12269.
• BREZGIN S ET AL. 2023. Technological aspects of manufacturing and analytical control of biological nanoparticles. Biotechnol Adv 64: 108122.
• BUZAS EI. 2022. The roles of extracellular vesicles in the immune system. Nat Rev Immunol 23: 1.
• CHEN J ET AL. 2022. Ensemble cryo-EM reveals conformational states of the nsp13 helicase in the SARS-CoV-2 helicase replication-transcription complex. Nat Struct Mol Biol 29(3): 250-260.
• CHEUNG W ET AL. 2010. Rotaviruses associate with cellular lipid droplet components to replicate in viroplasms, and compounds disrupting or blocking lipid droplets inhibit viroplasm formation and viral replication. J Virol 84: 6782-6798.
• CHOI D ET AL. 2022. Quantitative proteomics and biological activity of extracellular vesicles engineered to express SARS-CoV-2 spike protein. J Extracell Biol 1: 10.
• CHOW FW & MORPHEW RM. 2023. Extracellular vesicles in microbes, pathogens, and infectious diseases. Int J Mol Sci 24(13): 10686.
• COCOZZA F ET AL. 2020. Extracellular vesicles containing ACE2 efficiently prevent infection by SARS-CoV-2 spike protein-containing virus. J Extracell Vesicles 10: 2.
• COCUCCI E & MELDOLESI J. 2015. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol 25(6): 364-372.
• COFFEY CM, SHEH A, KIM IS, CHANDRAN K, NIBERT ML & PARKER JSL. 2006. Reovirus outer capsid protein μ1 induces apoptosis and associates with lipid droplets, endoplasmic reticulum, and mitochondria. J Virol 80(17): 8422-8438.
• COLOMBO M, RAPOSO G & THÉRY C. 2014. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Biol 30: 255-289.
• D’AVILA H ET AL. 2024. Lipid metabolism modulation during SARS-CoV-2 infection: a spotlight on extracellular vesicles and therapeutic prospects. Int J Mol Sci 25: 640.
• DIAS SSG ET AL. 2020. Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators. PLoS Pathog 16: e1009127.
• EL ANDALOUSSI S, MÄGER I, BREAKFIELD XO & WOOD MJA. 2013. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 12: 347-357.
• EL-SHENNAWY L ET AL. 2022. Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2. Nat Commun 13: 1.
• ESSALMANI R ET AL. 2022. Distinctive roles of furin and TMPRSS2 in SARS-CoV-2 infectivity. J Virol 96: 8.
• FANG Y ET AL. 2023. Mechanisms of potential therapeutic utilization of mesenchymal stem cells in COVID-19 treatment. Cell Transplant 32: 9636897231184611.
• FILIPE A & MCLAUCHLAN J. 2015. Hepatitis C virus and lipid droplets: finding a niche. Trends Mol Med 21: 34-42.
• FUJII K, HURLEY JH & FREED EO. 2007. Beyond Tsg101: the role of Alix in ‘ESCRTing’ HIV-1. Nat Rev Microbiol 5(12): 912-916.
• FUNG TS & LIU DX. 2019. The ER stress sensor IRE1 and MAP kinase ERK modulate autophagy induction in cells infected with coronavirus infectious bronchitis virus. Virology 533: 34-44.
• GARCIA-BELTRAN WF ET AL. 2022. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. Cell 185: 457-466.
• GENG F & GUO D. 2023. SREBF1/SREBP-1 concurrently regulates lipid synthesis and lipophagy to maintain lipid homeostasis and tumor growth. Autophagy 20(5): 1183-1185.
• GHOSH AK ET AL. 2021. Molecular and serological characterization of the SARS-CoV-2 delta variant in Bangladesh in 2021. Viruses 13: 2310.
• GOULD SJ, BOOTH AM & HILDRETH JEK. 2003. The Trojan exosome hypothesis. Proc Natl Acad Sci USA 100: 10592-10597.
• GOWEN A, SHAHJIN F, CHAND S, ODEGAARD KE & YELAMANCHILI SV. 2020. Mesenchymal stem cell-derived extracellular vesicles: challenges in clinical applications. Front Cell Dev Biol 8: 149.
• GYÖRGY B ET AL. 2011. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 68: 2667-2688.
• HA D, YANG N & NADITHE V. 2016. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sin B 6(4): 287-296.
• HAZAL N & GERLIER D. 2003. Virus entry, assembly, budding, and membrane rafts. Microbiol Mol Biol Rev 67: 226-237.
• HERNÁNDEZ G ET AL. 2023. Mutations in the RACGAP1 gene cause autosomal recessive congenital dyserythropoietic anemia type III. Haematologica 108: 581-587.
• HERNÁNDEZ-DÍAZCOUDER A, DÍAZ-GODÍNEZ C & CARRERO JC. 2023. Extracellular vesicles in COVID-19 prognosis, treatment, and vaccination: an update. Appl Microbiol Biotechnol 107: 2131-41.
• HILL AF. 2019. Extracellular vesicles and neurodegenerative diseases. J Neurosci 39: 9269-9273.
• HORN MD & MACLEAN AG. 2021. Extracellular vesicles as a means of viral immune evasion, CNS invasion, and glia-induced neurodegeneration. Front Cell Neurosci 15: 695899.
• HURLEY JH. 2015. ESCRTs are everywhere. EMBO J 34: 2398-2407.
• IZQUIERDO-USEROS N, NARANJO-GÓMEZ M, ERKIZIA I, PUERTAS MC, BORRÀS FE, BLANCO J & MARTINEZ-PICADO J. 2010. HIV and Mature Dendritic Cells: Trojan Exosomes Riding the Trojan Horse. PLoS Pathogens 6(3): e1000740.
• JAFARI D ET AL. 2019. The relationship between molecular content of mesenchymal stem cells derived exosomes and their potentials: opening the way for exosomes based therapeutics. Biochimie 165: 76-89.
• JEPPESEN DK ET AL. 2019. Reassessment of exosome composition. Cell 177: 428-445.
• JIA Y ET AL. 2022. Small extracellular vesicles isolation and separation: current techniques, pending questions and clinical applications. Theranostics 12: 6548-6575.
• KIM J & THAPA N. 2023. Exosome-based COVID-19 vaccine. Methods Mol Biol 2668: 301-311.
• KRISHNAN A, MUTHUSAMY S, FERNANDEZ FB & KASOJU N. 2022. Mesenchymal stem cell-derived extracellular vesicles in the management of COVID-19-associated lung injury: a review on publications, clinical trials and patent landscape. Tissue Eng Regen Med 19: 659-673.
• KUMAR A ET AL. 2020. Extracellular vesicles in viral replication and pathogenesis and their potential role in therapeutic intervention. Viruses 12: 887.
• KUMAR D, GUPTA D, SHANKAR S & SRIVASTAVA RK. 2014. Biomolecular characterization of exosomes released from cancer stem cells: possible implications for biomarker and treatment of cancer. Oncotarget 6: 5.
• KWON Y ET AL. 2020. Detection of viral RNA fragments in human iPSC cardiomyocytes following treatment with extracellular vesicles from SARS-CoV-2 coding sequence overexpressing lung epithelial cells. Stem Cell Res Ther 11: 1.
• LI SR, MAN QW, GAO X, LIN H, WANG J, SU FC, WANG HQ, BU LL, LIU B & CHEN G. 2021. Tissue-derived extracellular vesicles in cancers and non-cancer diseases: Present and future. J Extracell Vesicles 10(14): e12175.
• LIU MH, LIN XL & XIAO LL. 2024. SARS-CoV-2 nucleocapsid protein promotes TMAO-induced NLRP3 inflammasome activation by SCAP-SREBP signaling pathway. Tissue Cell 86: 102276.
• LIU YJ & WANG C. 2023. A review of the regulatory mechanisms of extracellular vesicles-mediated intercellular communication. Cell Commun Signal 21: 1.
• LYN RK, HOPE G, SHERRATT AR, MCLAUCHLAN J & PEZACKI JP. 2013. Bidirectional lipid droplet velocities are controlled by differential binding strengths of HCV core DII protein. PLoS ONE 8: e78065.
• MAAS SLN, BREAKFIELD XO & WEAVER AM. 2017. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol 27: 172-188.
• MALIK YA. 2020. Properties of Coronavirus and SARS-CoV-2. Malays J Pathol 42(1): 3-11.
• MARTIN C, LIGAT G & MALNOU CE. 2024. The Yin and the Yang of extracellular vesicles during viral infections. Biomed J 47(5): 100659.
• MATSUMOTO J, STEWART T, BANKS WA & ZHANG J. 2018. The transport mechanism of extracellular vesicles at the blood-brain barrier. Curr Pharm Des 23: 6206-6214.
• MATSUZAKA Y & YASHIRO R. 2023. Extracellular vesicle-based SARS-CoV-2 vaccine. Vaccines 11: 539.
• MENCK K ET AL. 2017. Neutral sphingomyelinases control extracellular vesicles budding from the plasma membrane. J Extracell Vesicles 6: 1378056.
• MORADINASAB S, POURBAGHERI-SIGAROUDI A, ZAFARI P, GHAFFARI SH & BASHASH D. 2021. Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles in COVID-19-induced ARDS: mechanisms of action, research progress, challenges, and opportunities. Int Immunopharmacol 97: 107694.
• MOTALEBBNEZHAD M ET AL. 2023. Potential therapeutic applications of extracellular vesicles in the immunopathogenesis of COVID-19. Pathol Res Pract 241: 154280.
• MURUGAN D & RANGASAMY L. 2022. Pooled evidence from preclinical and clinical studies for stem cell-based therapy in ARDS and COVID-19. Mol Cell Biochem 478(7): 1487-1518.
• NAIR S ET AL. 2023. Genomic communication via circulating extracellular vesicles and long-term health consequences of COVID-19. J Transl Med 21: 1.
• OLZMANN JA & CARVALHO P. 2019. Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol 20: 137-155.
• PATHAN M, FONSEKA P, CHITTI SV, KANG T, SANWLANI R, VAN DEUN J, HENDRIX A & MATHIVANAN S. 2019. Vesiclepedia 2019: a compendium of RNA, proteins, lipids and metabolites in extracellular vesicles. Nucleic Acids Res 47(D1): D516-D519.
• POCSFALVI G, MAMMADOVA R, RAMOS JUAREZ AP, BOKKA R, TREPICCIONE F & CAPASSO G. 2020. COVID-19 and extracellular vesicles: an intriguing interplay. Kidney Blood Press Res 45(5): 661-670.
• POPOWSKI KD ET AL. 2022. Inhalable dry powder mRNA vaccines based on extracellular vesicles. Matter 5: 2960-2974.
• PROAL AD & VANELZAKKER MB. 2021. Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms. Front Microbiol 12: 1.
• QU Y, WANG W, XIAO MZX, ZHENG Y & LIANG Q. 2023. The interplay between lipid droplets and virus infection. J Med Virol 95: e28967.
• RAAB-TRAUB N & DITTMER DP. 2017. Viral effects on the content and function of extracellular vesicles. Nat Rev Microbiol 15: 559-572.
• RAMASAMY S & SUBBIAN S. 2021. Critical determinants of cytokine storm and type I interferon response in COVID-19 pathogenesis. Clin Microbiol Rev 34: 3.
• REY-CADILHAC F, RACHENNE F, MISSÉ D & POMPON J. 2023. Viral components trafficking with(in) extracellular vesicles. Viruses 15(12): 2333.
• RIPON MAR, BHOWMIK DR, AMIN MT & HOSSAIN MS. 2021. Role of arachidonic cascade in COVID-19 infection: A review. PGLM 154: 106539.
• RUBIO-CASILLAS A, REDWAN EM & UVERSKY VN. 2022. SARS-CoV-2: A master of immune evasion. Biomedicines 10: 1339.
• SAMSA MM ET AL. 2009. Dengue virus capsid protein usurps lipid droplets for viral particle formation. PLoS Pathog 5: e1000632.
• SANTOS-LOPEZ G, CORTÉS-HERNÁNDEZ P, VALLEJO-RUIZ V & REYES-LEYVA J. 2021. SARS-CoV-2: basic concepts, origin and treatment advances. Gac Med Mex 157: 1.
• SCHNEIDER A & SIMONS M. 2013. Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders. Cell Tissue Res 352(1): 33-47.
• SENGUPTA V, SENGUPTA S, LAZO A, WOODS P, NOLAN A & BREMER N. 2020. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Stem Cells Dev 29: 747-754.
• SHI CS ET AL. 2014. SARS-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome. J Immunol 193: 3080-3089.
• SKOG J ET AL. 2008. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10: 1470-1476.
• SOARES VC ET AL. 2023. Inhibition of the SREBP pathway prevents SARS-CoV-2 replication and inflammasome activation. Life Sci Alliance 6: e202302049.
• SOLTANI-ZANGBAR MS ET AL. 2022. Immune system-related soluble mediators and COVID-19: basic mechanisms and clinical perspectives. Cell Commun Signal 20: 1.
• STATELLO L ET AL. 2018. Identification of RNA-binding proteins in exosomes capable of interacting with different types of RNA: RBP-facilitated transport of RNAs into exosomes. PLoS ONE 13(4): e0195969.
• SYED GH, AMAKO Y & SIDDIQUI A. 2010. Hepatitis C virus hijacks host lipid metabolism. Trends Endocrinol Metab 21: 33-40.
• TAKAHASHI T & SUZUKI T. 2011. Function of membrane rafts in viral lifecycles and host cellular response. Biochem Res Int 2011: 1-23.
• TEY SK & YAM JWP. 2022. The importance of activated TMPRSS2 in the proviral role of small extracellular vesicles in SARS-CoV-2 infection. J Extracell Vesicles 11: 12296.
• THÉRY C ET AL. 2018. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 7(1): 1535750.
• THÉRY C, ZITVOGEL L & AMIGORENA S. 2002. Exosomes: composition, biogenesis and function. Nat Rev Immunol 2: 569-579.
• TOYOFUKU M, NOMURA N & EBERL L. 2019. Types and origins of bacterial membrane vesicles. Nat Rev Microbiol 17: 13-24.
• TRAJKOVIC K ET AL. 2008. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319: 1244-1247.
• VAN DER POL E, BÖING AN, HARRISON P, STURK A & NIEUWLAND R. 2012. Classification, functions, and clinical relevance of extracellular vesicles. In: MATTSON MP (Ed), Pharmacol Rev 64: 676-705.
• VAN NIEL G, D’ANGELO G & RAPOSO G. 2018. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 19: 213-228.
• VERTA R ET AL. 2022. Generation of Spike-Extracellular Vesicles (S-EVs) as a tool to mimic SARS-CoV-2 interaction with host cells. Cells 11: 146.
• VILLAREAL VA, RODGERS MA, COSTELLO DA & YANG PL. 2015. Targeting host lipid synthesis and metabolism to inhibit dengue and hepatitis C viruses. Antiviral Res 124: 110-121.
• V’KOVSKI P, KRATZEL A, STEINER S, STALDER H & THIEL V. 2021. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol 19(3): 155-170.
• WANG Z, MO H, HE Z, CHEN A & CHENG P. 2022. Extracellular vesicles as an emerging drug delivery system for cancer treatment: current strategies and recent advances. Biomed Pharmacother 153: 113480.
• WEI W ET AL. 2020. Mesenchymal stem cell-derived exosomes: a promising biological tool in nanomedicine. Front Pharmacol 11: 590470.
• WEISBLUM Y ET AL. 2020. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. eLife 9: e61312.
• WELTE MA & GOULD AP. 2017. Lipid droplet functions beyond energy storage. Biochim Biophys Acta Mol Cell Biol Lipids 1862(10): 1260-1272.
• WU Z & MCGOOGAN JM. 2020. Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak in China. JAMA 323: 13.
• WURDINGER T, GATSON NN, BALAJ L, KAUR B, BREAKFIELD XO & PEGTEL DM. 2012. Extracellular vesicles and their convergence with viral pathways. Adv Virol 2012: 1-12.
• XIA B ET AL. 2023. Extracellular vesicles mediate antibody-resistant transmission of SARS-CoV-2. Cell Discov 9: 1.
• XIE F ET AL. 2021. Engineering extracellular vesicles enriched with palmitoylated ACE2 as COVID-19 therapy. Adv Mater 33: 2103471.
• YADAV R ET AL. 2021. Role of structural and non-structural proteins and therapeutic targets of SARS-CoV-2 for COVID-19. Cells 10: 821.
• YAN Y ET AL. 2021. The potential role of extracellular vesicles in COVID-19 treatment: opportunity and challenge. Front Mol Biosci 8: 699929.
• YE Q, WANG B & MAO J. 2020. The pathogenesis and treatment of the ‘cytokine storm’ in COVID-19. J Infect 80: 6.
• YUAN S ET AL. 2021. SARS-CoV-2 exploits host DGAT and ADRP for efficient replication. Cell Discovery 7: 1.
• ZHANG C ET AL. 2017. Virus-triggered ATP release limits viral replication through facilitating IFN-β production in a P2X7-dependent manner. J Immunol 199: 1372-1381.
• ZHANG Q, JEPPESEN DK, HIGGINBOTHAM JN, FRANKLIN JL & COFFEY RJ. 2023. Comprehensive isolation of extracellular vesicles and nanoparticles. Nat Protoc 18: 1462-1487.
• ZHU X ET AL. 2021. Plasma extracellular vesicles carrying ACE2 act as decoys for SARS-CoV-2 and prevent infection. J Extracell Vesicles 10(8): e12124.

Publication Dates

• Publication in this collection
  12 May 2025
• Date of issue
  2025

History

• Received
  20 Oct 2024
• Accepted
  21 Jan 2025