Injectable Hydrogel for Cardiac Repair via Dual Inhibition of Ferroptosis and Oxidative Stress

Ferroptosis plays a significant role in ischemic heart disease by exacerbating myocardial injury through oxidative stress, iron metabolism disorder, and inflammation. Herein, we develop an injectable hydrogel (HSD/DFO@GMs) with antiferroptosis and antioxidant properties for cardiac repair. The hydrogel is composed of dopamine-grafted oxidized hyaluronic acid, adipic acid dihydrazide grafted hyaluronic acid, and deferoxamine loaded gelatin microsphere, connected via a dynamic Schiff base bond. This hydrogel exhibits a favorable injectability and stable mechanical properties. It effectively chelates Fe²⁺ and scavenges the reactive oxygen species (ROS), creating a conducive microenvironment for cardiac repair. The dynamic Schiff base bond and gelatin matrix respond to the weakly acidic and MMP-2-rich microenvironment postinjury, enabling on-demand release of DFO in the injured myocardium. In vitro experiments indicate that the hydrogel significantly inhibits the ferroptosis and oxidative stress damage in H9C2 cardiomyocytes under a hypoxia/reoxygenation microenvironment. In an in vivo ischemia-reperfusion model, the HSD/DFO@GMs hydrogel reduces oxidative stress, modulates intracellular labile iron pool levels, and promotes revascularization, ultimately improving cardiac function. Overall, the HSD/DFO@GMs hydrogel provides a new strategy to improve cardiac repair by inhibiting ferroptosis and mitigating oxidative stress damage.