Multi-stage cooperative ROS-responsive hydrogel platform for drug delivery in myocardial ischemia-reperfusion injury repair

Myocardial ischemia-reperfusion (I/R) injury is characterized by oxidative stress, mitochondrial dysfunction, inflammation, and fibrosis, ultimately leading to chronic cardiac dysfunction and heart failure. Current therapeutic strategies that predominantly target single biological pathways exhibit limited long-term efficacy, underscoring the necessity for multi-targeted approaches. In this study, we developed a ROS-responsive hydrogel system, S1&FT/Lipo-QCFT, tailored to deliver drugs for treating various stages of myocardial I/R injury. This system timing of drug release to achieve rapid deployment at early intervention stages and maintain sustained release thereafter. Initially, the hydrogel platform quickly releases the molecular forms of the superoxide inhibitor S1QEL1.1 and tannic acid, specifically targeting the elevated ROS levels at the I/R site to alleviate early oxidative damage and encourage macrophage polarization toward the M2 phenotype. Subsequently, the system gradually releases anti-fibrotic agent FT011, encapsulated in lipid nanocarriers, which actively counters TGF-β1-induced fibrosis and forestalls adverse ventricular remodeling, thereby enhancing long-term cardiac repair. In vivo studies demonstrated that the S1&FT/Lipo-QCFT hydrogel significantly improved cardiac function and reduced adverse ventricular remodeling. This hydrogel system provides a promising multi-targeted therapeutic strategy for comprehensive myocardial I/R injury treatment with strong potential for clinical translation.