Fabrication of a conductive, ionic liquid functionalized, oxygen-generating hydrogel loaded with ADSC-derived exosomes to enhance angiogenesis and cardiac repair after acute myocardial infarction

Acute myocardial infarction (AMI) remains one of the most severe and life-threatening cardiac diseases, accounting for a substantial proportion of mortality worldwide and necessitating the development of novel treatment approaches for effective myocardial repair. Biocompatible, ionically conductive injectable hydrogel scaffolds have emerged as promising candidates for AMI treatment owing to their prominent electrical conductivity and mechanical compatibility with cardiac tissue. <b>Methods:</b> In the present investigation, a facile ionic-conductive injectable hydrogel was developed by incorporating the conductive polymer PEDOT and boronic acid-functionalized carboxymethyl chitosan (pCMC) with poly-ionic liquid (P-ILs), oxygen-generating calcium peroxide (CaO₂) particles, and adipose-derived stem cell exosomes (ADSC-exos) to improve myocardial regeneration via enhancing conductivity and oxygen release. The physiological and mechanical characteristics of the injectable hydrogel were examined through morphological evaluation, oxygen-release profiling, electroactivity, and rheological analysis. <i>In vitro</i> biocompatibility was assessed using rat cardiac fibroblasts (RCF) and H9C2 cells. For <i>in vivo</i> investigation, a rat ischemia-reperfusion model was established, and the developed hydrogels were administered for 28 days to examine cardiac function recovery and myocardial regeneration. <b>Results:</b> The encapsulation of Exo within the hydrogel enhanced its biological performance by promoting antioxidant activity and angiogenesis, while concurrently inhibiting cardiomyocyte (CM) apoptosis and inflammation. Both <i>in vitro</i> and <i>in vivo</i> findings demonstrated that the Exo-loaded ICon-O₂-hydrogel significantly enhanced reactive oxygen species (ROS) scavenging, cellular proliferation, migration, angiogenesis responses, resulting in effective myocardial repair, accelerated cardiac functional recovery, reduced fibrosis, and increased neovascularization in the rat model. <b>Conclusion:</b> The combined therapeutic model integrating ADSC-exos with an oxygen-generating ionic-conductive hydrogel demonstrates a promising potential for AMI therapy by reducing fibrosis and scar formation while promoting angiogenesis and myocardial regeneration.