Celastrol‐Loaded Conductive Hydrogel Mitigates Myocardial Ischemia‐Reperfusion Injury and Restores Electrophysiological Function

ABSTRACT Myocardial ischemia–reperfusion injury (MIRI) remains an unresolved clinical challenge that severely limits the prognosis of patients undergoing revascularization. Through a phenotype‐guided antioxidant screening workflow, celastrol (CLT) was selected as a bioactive compound for integration into a locally retained conductive hydrogel platform. However, the clinical translation of CLT is limited by poor aqueous solubility and potential systemic toxicity. To overcome these limitations, we developed an injectable F127DA/GelMA/PEDOT:PSS/celastrol hydrogel (FGPC) for the localized and sustained delivery of CLT. The FGPC hydrogel, composed of Gelatin methacryloyl (GelMA), Pluronic F127 diacrylate (F127DA) , and conductive poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), exhibits favorable mechanical properties, enhanced electrical conductivity, local retention, and controlled drug release. In vitro, FGPC effectively reduced reactive oxygen species (ROS), supported cardiomyocyte structural organization, and enhanced gap‐junction coupling. In a rat MIRI model, local FGPC delivery attenuated acute oxidative stress, suppressed inflammatory activation, and reduced neutrophil extracellular trap formation. Transcriptomic analysis further revealed downregulation of inflammatory pathways, including the IL‐17 signaling pathway and S100a8/S100a9‐related inflammatory mediators. During the chronic repair phase, FGPC improved cardiac function, reduced fibrosis, restored connexin 43 expression, reduced inducible ventricular arrhythmia susceptibility, and promoted angiogenesis without obvious systemic toxicity. This study presents a locally retained conductive hydrogel platform that combines CLT‐mediated microenvironment modulation with electrical support, providing a potential strategy for myocardial repair after reperfusion.