Engineered exosomes encapsulated miR-218-5p alleviate the progression of PM2.5-induced epithelial-mesenchymal transition via ferroptosis pathway

Air pollution represents the greatest global environmental risk to human health, particularly regarding pulmonary fibrosis. Among atmospheric pollutants, airborne fine particulate matter (PM2.5) contributes most significantly to global mortality and disease burden. The epithelial-mesenchymal transition (EMT) constitutes a critical process in PM2.5-induced pulmonary fibrosis, concomitant with iron deposition and disrupted lipid peroxide metabolism. We found that PM2.5-induced ferroptosis contributes to EMT in lung tissue of mice after PM2.5 exposure. An in vitro macrophage-epithelial cell co-culture model demonstrated that exosomes from PM2.5-exposed macrophage induced ferroptosis, thereby driving EMT in epithelial cells. Pharmacological inhibition of the HO-1, which is involved in ferroptosis regulation significantly reversed the EMT alterations. Crucially, miR-218-5p was identified as a potential macrophage-derived exosomal miRNA targeting HO-1 to mediate ferroptosis-driven EMT in epithelial cells. Furthermore, engineered exosomes encapsulating miR-218-5p were constructed and administered via nebulization to alleviate PM2.5-induced pulmonary fibrosis in mice. In summary, this work provides experimental evidence supporting a targeted delivery strategy against PM2.5-induced pulmonary fibrosis.