Extracellular Vesicles from Mesenchymal Stromal Cells as a Promising Therapy for ARDS: A Systematic Review of Preclinical Studies

Samuel Couto¹Miqueias Lopes-Pacheco²Vanderson Rocha¹Claudia C Dos Santos³Patricia R. M. Rocco^4*

• ¹Universidade de Sao Paulo, São Paulo, Brazil
• ²Emory University School of Medicine, Atlanta, United States
• ³University of Toronto, Toronto, Canada
• ⁴Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic strategy for acute respiratory distress syndrome (ARDS), a condition with limited effective treatment options. This systematic review synthesizes findings from 51 in vivo preclinical studies investigating the efficacy, delivery methods, mechanisms of action, and optimization strategies of MSC-EV interventions in experimental ARDS. Across diverse models and etiologies, MSC-EVs consistently attenuated inflammation, improved gas exchange, and enhanced survival. Mechanistically, these benefits were largely attributed to microRNA-mediated immunomodulation, including promotion of anti-inflammatory macrophage phenotypes and improved bacterial clearance. Factors influencing therapeutic efficacy included the MSC source, EV preconditioning, timing of administration, and route of delivery. Despite these encouraging findings, critical methodological heterogeneity limits reproducibility and translational potential. This heterogeneity is particularly evident in dose metrics (e.g., particle number versus protein content), EV quantification methods (e.g., flow cytometry versus nanoparticle tracking analysis), and timing of outcome assessment. This review underscores the growing body of preclinical evidence supporting MSC-EVs in ARDS and identifies key knowledge gaps—such as optimal dosing, safety profiling, and scalable manufacturing—that must be addressed to enable clinical translation.