Severe COVID-19 and bacterial sepsis share clinical manifestations of systemic inflammation and organ dysfunction. Yet, early differentiation between these conditions and timely identification of patients at risk of deterioration remain major clinical challenges. Extracellular vesicle (EV)-associated microRNAs (miRNAs) have emerged as promising biomarkers of host immune dysregulation. In our study, we have characterized circulating EV-miRNAs in patients with COVID-19, bacterial sepsis, localized bacterial infections, and healthy subjects to assess their diagnostic and prognostic utility. After EV isolation from plasma and characterization by nanoparticle tracking analysis and flow cytometry, a panel of 12 inflammation-related miRNAs were individually quantified by qRT-PCR. Four EV-miRNAs—miR-28-5p, miR-199a-5p, miR-200a-3p, and miR-369-3p—were significantly elevated in COVID-19 patients, with higher levels in those with poor prognosis. miR-199a-5p and miR-200a-3p were increased in bacterial sepsis compared with COVID-19, enabling discrimination between viral and bacterial sepsis. Three EV-miRNAs—miR-28-5p, miR-199a-5p, and miR-200a-3p—were markedly higher in bacterial sepsis than localized infections, and ROC analysis showed a strong diagnostic performance, particularly for miR-199a-5p, alone or in combination with other EV-miRNAs. The increased expression of selected EV-miRNAs was associated with higher SOFA scores and in-hospital mortality. These findings indicate that EV-miRNAs reflect pathogen-specific and severity-related immune responses, supporting their potential as minimally invasive biomarkers for early diagnosis and risk stratification in severe infections.

Sepsis remains a leading cause of mortality worldwide and is increasingly recognized as a syndrome of dynamic immune dysregulation rather than a uniform inflammatory condition. The traditional paradigm of sequential hyperinflammation followed by immunosuppression has been replaced by a more complex view in which these processes coexist and evolve over time, contributing to marked interindividual variability in clinical outcomes. Despite advances in supportive care, current diagnostic and therapeutic approaches are still largely non-specific and fail to account for this biological heterogeneity. Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication and potential integrators of immune activity in sepsis. These nanosized particles carry proteins, nucleic acids, lipids, and metabolites that reflect the functional state of their cells of origin and actively participate in immune regulation. Experimental and clinical evidence indicate that EVs exert context-dependent effects, contributing both to the propagation of inflammatory processes and the establishment of immunosuppressive states through the transfer of regulatory signals. Beyond their mechanistic role, EVs represent a promising platform for immune monitoring. Their cell-specific and dynamic molecular signatures have been associated with disease severity, organ dysfunction, and clinical trajectories, suggesting their role as biomarkers for patient stratification. In parallel, engineered and stem cell-derived EVs are being explored as therapeutic vectors capable of modulating immune responses and restoring immune homeostasis. In this review, we examine current concepts of immune dysregulation in sepsis and discuss how EVs may serve as both mediators and decoders of immune heterogeneity. We propose that EV-based approaches could bridge the gap between high-dimensional immunological profiling and precision immunotherapy, enabling more adaptive and individualized management of septic patients.