Myocardial Infarction Treatment with a Composite Hydrogel Containing Metformin-Induced Vesicles of Adipose-Derived Stem Cells

Myocardial infarction (MI) leads to irreversible cardiomyocyte loss and adverse remodeling. Mesenchymal stem cell-derived extracellular vesicles (EVs) have shown promise in cardiac repair, but their clinical translation has been strictly limited by the short retention time and rapid clearance phenomena at the injury site. Metformin preconditioning of adipose-derived stem cells (ADSCs) is an effective way to enhance the yield of the EVs (Met-EVs). In this study, we incorporated Met-EVs into a composite hydrogel composed of decellularized extracellular matrices (dECMs) derived from porcine cardiac muscle and aortic adventitia, enabling sustained EV release and attenuation of after MI inflammation. In a rat MI model, the Met-EVs-laden dECM hydrogel (Met-EVs-dECM) significantly improved cardiac function recovery by enhancing cardiomyocyte survival, reducing cardiac apoptosis, and promoting angiogenesis. C1q/tumor necrosis factor-related protein 1 was identified as a contributor to the biological effects of Met-EVs, at least in part through PI3K/AKT signaling. Collectively, these findings demonstrate the therapeutic potential of the Met-EV-loaded dECM hydrogel for myocardial repair after MI.