Hydrogel Crosslinked by Chiral Bioactive Peptides for Synergistic Oxidative Stress Scavenging and Targeted Anti‐Fibrotic Therapy After Myocardial Infarction

ABSTRACT Myocardial infarction (MI) triggers a cascade of pathological processes characterized by oxidative stress and fibrotic scar formation, yet existing multi‐stage repair materials face challenges including complex compositions, uncontrollable degradation, and insufficient targeting specificity. This study develops the hydrogel system composed of chiral bioactive peptides (L/D gel@DPFR) by integrating chiral antioxidant peptide to enhance hydrogel stability and enable controlled degradation, while further incorporating cardiac fibroblast‐targeted peptide‐modified nanoparticles loaded with Repsox (a TGF‐β inhibitor). In vitro and in vivo experimental results demonstrate that D gel@DPFR exhibits a slower degradation rate than L gel@DPFR, enabling prolonged regulation of oxidative stress and apoptosis reduction, while facilitating orderly release of DPFR nanoparticles to effectively suppress type I and III collagen deposition and alleviate myocardial fibrosis. Overall, this study first elucidates the differential effects and mechanisms of multifunctional peptide hydrogels constructed based on a chiral bioactive peptide regulation strategy in myocardial repair. Compared to L gel@DPFR, D gel@DPFR establishes an effective “early antioxidant‐late antifibrotic” synergistic repair system for MI, demonstrating more favorable therapeutic effects in regulating the pathological microenvironment. These findings offer novel design strategies for multi‐stage coordinated repair peptide hydrogels targeting MI pathological conditions.