MSCs/EVs-based therapy targeting DAD: research progress and future perspectives from ARDS and COVID-19 to RP-ILD.

Diffuse alveolar damage (DAD) is the core pathological process of acute lung injury, characterized by dual injury to alveolar epithelial and capillary endothelial cells, initiation of an inflammatory storm, and subsequent fibrotic remodeling, with persistently high clinical mortality. This pathological change is not restricted to a single disease but widely exists in critical pulmonary disorders such as acute respiratory distress syndrome (ARDS), severe COVID-19, and rapidly progressive interstitial lung disease (RP-ILD), acting as a key driver of disease progression. In recent years, mesenchymal stromal cells (MSCs) and their derived extracellular vesicles (EVs) have become research hotspots for their superior immunomodulatory, anti-apoptotic, tissue-repair, and anti-fibrotic properties. Based on the DAD pathological framework, this article systematically correlates epithelial barrier injury, inflammatory cascade amplification and pulmonary fibrotic remodeling with the therapeutic mechanisms of MSCs and their derived EVs in ARDS, COVID-19 and RP-ILD. It aims to provide a solid basis for the clinical translation of MSCs- and EVs-based therapies and promote their development into a mechanism-driven therapeutic paradigm targeting DAD, with great clinical value and academic innovation.