Hypoxia-preconditioned MiotEVs from bone marrow mesenchymal stem cells inhibit myocardial infarction-induced cardiac fibrosis.

Hypoxia-preconditioned bone marrow mesenchymal stem cell-derived mitochondrial extracellular vesicles (Hypoxia-BMSC MitoEVs) emerged as a novel therapeutic candidate for myocardial infarction (MI)-induced cardiac fibrosis. Here, we demonstrate that MitoEVs isolated from hypoxic BMSCs, rich in intact mitochondria and the RNA-binding protein Quaking (QKI), potently inhibited TGF-β1-driven myofibroblast activation in vitro by suppressing α-SMA and collagen expression while restoring mitochondrial oxidative phosphorylation and metabolic balance. In a murine MI model, systemic delivery of Hypoxia-BMSC MitoEVs attenuated cardiac fibrosis, reduced infarct size, and improved left ventricular function. Pharmacological inhibition of mitochondrial ATP synthase in MitoEVs similarly diminished their therapeutic efficacy. Mechanistically, MitoEVs delivered QKI protein to cardiac fibroblasts, where it inhibited translation of fibrotic mRNAs via m7G-modified RNA interactions. Genetic ablation of QKI in BMSCs abrogated MitoEV-mediated antifibrotic effects both in vitro and in vivo, confirming QKI as a critical effector. These results suggested that both QKI-driven translational suppression and mitochondrial bioenergetics underpin their antifibrotic action. These findings highlight Hypoxia-BMSC MitoEVs as a therapeutic strategy to mitigate post-MI fibrosis, warranting further exploration for clinical translation.