Bone marrow mesenchymal stem cell-derived exosomes deliver miR-21a-5p to alleviate paraquat-induced acute lung injury by regulating endoplasmic reticulum-mitochondria contacts and pyroptosis in alveolar macrophages.

Paraquat-induced acute lung injury (ALI) is characterized by a high mortality rate and the absence of effective treatment options. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) possess therapeutic potential in tissue repair and the regulation of inflammation, but the molecular pathways underlying these actions are still poorly understood. This study aimed to clarify whether BMSC-Exos protect lung tissue by delivering miR-21a-5p to modulate endoplasmic reticulum-mitochondria contact sites (ERMCSs) in alveolar macrophages. Using a mouse model of paraquat-induced ALI, we intervened with BMSC-Exos and a miR-21a-5p inhibitor and systematically evaluated inflammatory response, pyroptosis signaling, and mitochondrial homeostasis via molecular biology, ultrastructure, electrophysiology, and metabolomics. BMSC-Exos promoted the formation of ERMCSs by increasing Mfn2 and VDAC1 expression, which consequently improved mitochondrial function and restrained NLRP3-Caspase-1-GSDMD-dependent pyroptosis. Disruption of ERMCSs abolished these protective effects. This study reveals a novel mechanism through which BMSC-Exos reprogram macrophage metabolism via miR-21a-5p delivery and suggests new targets for precision therapy in acute toxic lung injury.