Extracellular Vesicles as Molecular Regulators of Viral Infection: Implications for COVID-19 and Future Viral...

Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), exposed critical gaps in global preparedness for rapidly evolving viral pandemics. Though current antiviral treatments have shown some efficacy in managing COVID-19, substantial limitations, such as inefficient targeted drug delivery, aberrant host immune responses, and inadequate preparedness for future viral pandemics, were also evident. These challenges underscore the urgent need for target-specific, precise and efficient therapeutic strategies to modulate viral entry and immune dysregulation. Extracellular vesicles (EVs), cell-released cargo-carrying nanoscale vesicles, can both facilitate and inhibit viral infection depending on their cargo composition. Thus, endogenous EVs can promote or inhibit COVID-19 pathogenesis by modulating critical pathways, including angiotensin-converting enzyme 2 (ACE2)-mediated viral entry, transmembrane protease serine 2 (TMPRSS2)- dependent spike protein activation, nuclear factor kappa B (NF-κB)-driven inflammatory signaling, and NLRP3 inflammasome activation. In contrast, engineered EVs, such as ACE2-expressing EVs, mesenchymal stem cell-derived EVs and microRNA-enriched EVs, have therapeutic potential as they can facilitate antiviral defense through immune modulation, viral neutralization and suppression of cytokine storm. Moreover, EV-associated nucleic acids, proteins and lipids can act as biomarkers for disease detection and severity stratification. A deeper understanding of EV-virus mechanistic insights can enhance preparedness for similar viral diseases. In this review, we provide a comprehensive analysis of the molecular mechanisms underlying EV-virus interactions highlighting the therapeutic and diagnostic potential of EVs in tackling COVID-19 and future viral pandemics.