ROS-Responsive Hydrogel for Spatiotemporal Cascade Regulation of Ferroptosis and Fibrosis for Myocardial Protection

Abstract

Myocardial infarction (MI)-induced cardiac injury is mainly divided into two phases: the acute necrotic phase and the repair phase. Given the distinct therapeutic requirements of each phase—salvaging dying cardiomyocytes and reducing infarct size in the acute phase, while achieving controlled fibrosis to promote effective ventricular remodeling in the repair phase—we designed an ROS-responsive hydrogel co-delivery system (Met/Anti-34a@Gel) loaded with metformin (Met) and Anti-34a liposomes (Anti-34a Lip) to achieve precise regulation of both the acute and repair phases of MI. In the highly oxidative stress microenvironment following MI, the hydrogel gradually degrades and releases Met and Anti-34a Lip in a stage-specific manner. Met improves mitochondrial function, inhibits oxidative stress and ferroptosis, thereby effectively salvaging cardiomyocytes in the acute phase. Anti-34a Lip modulates the differentiation behavior of cardiac fibroblasts, suppressing excessive fibrosis and promoting favorable ventricular remodeling in the repair phase. Echocardiography revealed that Met/Anti-34a@Gel preserved left ventricular ejection fraction (EF) and fractional shortening (FS) at 72 h post-MI, reduced serum MDA levels in the acute phase, and maintained EF at approximately 60.92 ± 8.37% with a lower collagen I/III ratio at 4 weeks, collectively demonstrating both acute cardioprotection and long-term anti-fibrotic remodeling. In this combined therapeutic strategy, the early mitochondrial protection and anti-ferroptosis effects establish a favorable tissue and functional foundation for subsequent precision anti-fibrotic therapy, while the later anti-fibrotic treatment further consolidates the early protective effects. The two actions synergistically form a positive feedback loop, ultimately achieving sustained long-term cardiac functional improvement.