Engineered exosomes encapsulated miR-218-5p alleviate the progression of PM_2.5-induced epithelial-mesenchymal...

Air pollution represents the greatest global environmental risk to human health, particularly regarding pulmonary fibrosis. Among atmospheric pollutants, airborne fine particulate matter (PM_2.5) contributes most significantly to global mortality and disease burden. The epithelial-mesenchymal transition (EMT) constitutes a critical process in PM_2.5-induced pulmonary fibrosis, concomitant with iron deposition and disrupted lipid peroxide metabolism. We found that PM_2.5-induced ferroptosis contributes to EMT in lung tissue of mice after PM_2.5 exposure. An in vitro macrophage-epithelial cell co-culture model demonstrated that exosomes from PM_2.5-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 PM_2.5-induced pulmonary fibrosis in mice. In summary, this work provides experimental evidence supporting a targeted delivery strategy against PM_2.5-induced pulmonary fibrosis.