Sustained delivery of running-derived exosomes improves heart function after myocardial infarction

Exercise confers profound cardioprotective effects, yet the molecular mediators underlying its benefits remain incompletely understood. Emerging evidence suggests that circulating exosomes released during exercise carry bioactive cargos capable of modulating cardiac repair. In this study, we demonstrate that exosomes derived from exercise-conditioned mice (Exos) markedly enhance post-infarction cardiac recovery. Comprehensive metabolomic and proteomic profiling revealed that exercise reprograms exosomal contents, enriching metabolites and proteins involved in angiogenesis, oxidative stress defense, and iron metabolism. In a murine model of myocardial infarction, administration of exercise-derived exosomes significantly improved left ventricular function, reduced fibrosis, and attenuated pathological remodeling. Mechanistically, these exosomes promoted endothelial cell proliferation and migration, enhanced neovascularization, and activated the AKT/eNOS signaling cascade. Furthermore, they effectively inhibited cardiomyocyte ferroptosis by upregulating xCT, GPX4, and FTH1, thereby maintaining mitochondrial integrity and reducing lipid peroxidation. To enhance local retention and therapeutic efficacy, exosomes were delivered using a biocompatible hydrogel matrix, which provided sustained release but did not alter exosome bioactivity. Collectively, our findings identify exercise-derived exosomes as potent natural mediators of cardiac regeneration and reveal that their cardioprotective effects are mediated through the coordinated activation of angiogenic and anti-ferroptotic pathways. These insights highlight the translational potential of harnessing endogenous exercise-induced vesicles as a novel therapeutic strategy for myocardial infarction.TOC