Extracellular Vesicles as Drivers of Lung Endothelial Dysfunction in ARDS: Mechanisms and Therapeutic Opportunities

Acute respiratory distress syndrome (ARDS) is a complex, life-threatening condition that can arise from both direct pulmonary insults-such as pneumonia and aspiration-and indirect extrapulmonary causes including sepsis and trauma. A key driver of ARDS pathogenesis is the disruption of the lung endothelial barrier. Over the past several decades, extensive research has elucidated numerous mechanisms underlying the endothelial cell (EC) dysfunction in the acute lung injury (ALI) pathophysiology that occurs during ARDS. A range of EC modulators have been identified, as well as therapeutic strategies aimed at restoring EC integrity. More recently, extracellular vesicles (EVs) have emerged as critical mediators in ARDS pathogenesis, acting as potent regulators of endothelial function. EVs originating either locally in the lung or from distant tissues can reach the pulmonary vasculature, where they amplify inflammatory signaling and disrupt EC barrier integrity, thereby exacerbating injury and disease severity. This review summarizes recent advances in understanding how EVs from diverse cellular, tissue, and organ sources contribute to endothelial dysfunction in ALI pathophysiology. It also explores emerging endothelial-targeted therapies for ARDS, spanning preclinical and clinical stages, that may counteract EV-mediated pathogenic mechanisms, and highlights key gaps that remain to be addressed.