Exercise-primed exosomes in an injectable hydrogel promote myocardial repair via angiogenesis and ferroptosis inhibition

Myocardial infarction (MI) is a leading global cause of mortality and morbidity, with current therapies failing to achieve effective cardiac regeneration. Exercise-derived exosomes (Exos) hold great promise for cardioprotection, yet their clinical translation is severely hindered by rapid in vivo clearance and poor retention in infarcted myocardial tissue. Herein, we engineered an injectable polyethylene glycol-based hydrogel (Gel-PEG) as a localized and sustained delivery platform for exercise-derived exosomes (Exos@Gel-PEG), and systematically characterized the hydrogel's physicochemical, mechanical and biocompatibility properties, as well as exosome encapsulation efficiency and release kinetics. The association between exercise exosomes and ferroptosis of cardiomyocytes and vascular biology was determined through multi-omics analysis (metabolomics and proteomics). The therapeutic efficacy and underlying mechanisms of Exos@Gel-PEG were evaluated in a murine MI model, and the results demonstrated that Exos@Gel-PEG exhibited excellent injectability, biocompatibility and a sustained exosome release profile for up to 28 days in vitro, with significantly improved exosome retention in the infarcted heart for 15 days in vivo compared to free exosomes. In vivo, Exos@Gel-PEG treatment markedly improved cardiac systolic function, reduced myocardial interstitial fibrosis, and attenuated adverse ventricular remodeling in MI mice. Mechanistically, Exos@Gel-PEG activated the AKT/eNOS signaling pathway to promote endothelial cell proliferation, migration and post-infarction angiogenesis, and modulated myocardial iron homeostasis and oxidative stress to upregulate the expression of anti-ferroptotic proteins (xCT, GPX4, FTH1), thereby effectively suppressing cardiomyocyte ferroptosis. Furthermore, Exos@Gel-PEG showed no systemic toxicity and good in vivo biosafety. Collectively, our findings highlight that the Exos@Gel-PEG system integrates the cardioprotective merits of exercise-derived exosomes with the sustained delivery advantages of Gel-PEG, and exerts myocardial repair effects via dual mechanisms of angiogenesis promotion and ferroptosis inhibition, representing a novel and promising biomaterial-based therapeutic strategy for MI with potential clinical translation value.