Ammonium Persulfate-Loaded Carboxylic Gelatin–Methacrylate Nanoparticles Promote Cardiac Repair by Activating Epicardial Epithelial–Mesenchymal Transition via Autophagy and the mTOR Pathway

Restoring damaged myocardial tissue with therapeutic exogenous cells still has some limitations, such as immunological rejection, immature cardiac properties, risk of tumorigenicity, and a low cell survival rate in the ischemic myocardium microenvironment. Activating the endogenous stem cells with functional biomaterials might overcome these limitations. Research has highlighted the multiple differentiation potential of epicardial cells via epithelial–mesenchymal transition (EMT) in both heart development and cardiac regeneration. In our previous research, a carboxylic gelatin–methacrylate (carbox-GelMA) nanoparticle (NP) was fabricated to carry ammonium persulfate (APS), and APS-loaded carbox-GelMA NPs (NPs/APS) could drive the EMT of MCF-7 cells in vitro and promote cancer cell migration and invasion in vivo. The present study explored the roles of functional NPs/APS in the EMT of Wilms' tumor 1-positive (WT1+) epicardial cells and in the repair of myocardial infarction (MI). The WT1+ epicardial cells transformed into endothelial-like cells after being treated with NPs/APS in vitro, and the cardiac functions were improved significantly after injecting NPs/APS into the infarcted hearts in vivo. Furthermore, simultaneous activation of both autophagy and the mTOR pathway was confirmed during the NPs/APS-induced EMT process in WT1+ epicardial cells. Together, this study highlights the function of NPs/APS in the repair of MI.