ROS-differentiated release of Apelin-13 from hydrogel comprehensively treats myocardial ischemia-reperfusion injury

Treatment of myocardial ischemia-reperfusion (MI/R) injury still faces the lack of clinically approved drugs. Apelin-13 is a highly promising drug candidate of MI/R injury, but hampered by its extremely short half-life in plasma. This calls for efficient and smart delivering system for Apelin-13 delivery, but has not been reported. Herein, a reactive oxygen species (ROS)-responsive hydrogelator YFF-TK-FFY is designed, which co-assembles with Apelin-13 to form the peptide hydrogel Apelin-13@Gel TK. This hydrogel responds to ROS at varying levels in the surrounding environment of MI/R and releases Apelin-13 at different rates. In an MI/R injury mouse model, Apelin-13@Gel TK rapidly releases Apelin-13 in response to the high ROS in the core area of MI/R injury, efficiently reducing cardiomyocyte apoptosis within three days. In the ROS-low border zone, Apelin-13@Gel TK provides a slow and sustained release of Apelin-13, promoting angiogenesis and lymphatic remodeling, and facilitating the resolution of inflammation in the later repair stage after MI/R injury. By offering a spatiotemporally controlled drug release in response to ROS gradients in the MI/R microenvironment, this smart hydrogel presents a promising therapeutic strategy for effective treatment of MI/R injury.