Bifunctional Peptide Amphiphile Hydrogel Orchestrates Concerted Antioxidant and Anti‐Inflammatory Actions to Counter Myocardial Ischemia/Reperfusion Injury

Myocardial ischaemia/reperfusion injury presents significant clinical challenges driven by a self-perpetuating cycle of oxidative stress and inflammation. Current therapeutic strategies fail to simultaneously address these interconnected pathological events. Here, we present T&A-Gel, a supramolecular peptide amphiphile hydrogel integrating α-tocopherol and Angiotensin-(1-7) (Ang-(1-7)) through covalent conjugation to enable localized co-delivery and synergistically disrupt this oxidative-inflammatory feed-forward circuit. Upon hierarchical self-assembly into filamentous nanofibres, T&A-Gel forms a sustained-release depot that exposes Ang-(1-7) moieties while sequestering hydrophobic α-tocopherol. This design enables α-tocopherol to scavenge excess reactive oxygen species, ameliorating oxidative mitochondrial dysfunction and reducing cardiomyocyte apoptosis, while exposed Ang-(1-7) acts as a selective Mas receptor (MasR) agonist, activating the protective MasR/PI3K/Akt signaling axis. This dual-action mechanism suppresses NF-κB nuclear translocation and inhibits pro-inflammatory cytokine cascades. In vitro, T&A-Gel significantly enhanced hypoxia/reoxygenation-injured cardiomyocyte viability. In vivo, T&A-Gel demonstrated prolonged retention with substantial reduction in infarct size and cardiac necrosis biomarkers. Quantitative analysis confirmed substantial attenuation of interstitial fibrosis and cardiomyocyte hypertrophy, translating into restored ejection fraction and reduced ventricular dilation with excellent biocompatibility. These findings establish injectable supramolecular hydrogels as a powerful strategy for disrupting the interconnected injury cascade via mechanistically complementary payloads, offering a paradigm for precision cardioprotection.