Exosomes loaded stimuli responsive conductive hydrogel restores cardiac function post-myocardial infarction via SIRT1/p53-mediated anti-inflammatory mechanism: Mechanistic insights into cardioprotection.

Myocardial infarction (MI) is considered as a major cause of mortality globally, prominence the need for novel therapies to enhance cardiac repair. Conventional treatments offer inadequate restoration of the heart's intrinsic electrical and biological functions. In the present study, we developed a conductive, bioactive hydrogel composed of poly acrylic acid (PAA) and polypyrrole (PPy), loaded with exosomes (Exo@PAA/PPy-Hg), to improve cardiac regeneration post-MI. The fabricated hydrogel efficiently restored electrical conductivity and supported biological signaling within myocardial tissue. The hydrogel displayed controlled release of exosomes, biodegradability, and high compatibility. In vitro studies demonstrated excellent biocompatibility, with enhanced migration, tube formation and proliferation of HUVECs cells and H9C2 cardiomyocytes respectively. Further, Exo@PAA/PPy-Hg was evaluated for its ability to diminish OGD induced apoptosis and promote myocardial cell survival and regeneration. The findings displayed that, Exo@PAA/PPy-Hg significantly decline the apoptosis in H9C2 cells compared to others. In both in vitro and in vivo models, Exo@PAA/PPy-Hg enhanced cardiac function by encouraging electrical connectivity, reducing inflammation, and stimulating angiogenesis. Gene expression analysis revealed upregulation of angiogenic markers. Furthermore, Exo@PAA/PPy-Hg significantly improved left ventricular ejection fraction, reduced fibrosis, and enhanced neovascularization. Western blot and qRT-PCR analysis confirmed the modulation of the SIRT1/p53 pathway, reducing ferroptosis-induced cardiomyocyte death. These findings stated that exosome loaded conductive hydrogels offer a multifunctional and effective platform for myocardial infarction therapy.