Innovative hydrogel systems for antioxidant and cardiac protection after myocardial infarction: addressing Ferrostatin-1 solubility and retention challenges.

Myocardial infarction (MI) triggers severe oxidative stress and ferroptosis, leading to progressive cardiomyocyte death and impaired cardiac function. Inhibiting ferroptosis in ischemic myocardium with Ferrostatin-1 (Fer-1) shows potential in reducing oxidative stress and preserving cardiac function after MI. To address the challenges of Fer-1's poor water solubility and low cardiac retention, we developed an innovative injectable hydrogel system for synchronized antioxidant and ferroptosis-inhibiting therapy. Fer-1 was first encapsulated into liposomes (Lipo@Fer-1) to enhance its solubility and bioavailability. Then the liposomes were integrated into a degradable hydrogel composed of oxidized dextran and thiol-modified poly (γ-glutamic acid) (PS-OD-Lipo@Fer-1). The hydrogel aims to prolong the retention of Fer-1 around the infarct area while leveraging the inherent ROS-scavenging ability of the hydrogel. In experiments in vitro, Lipo@Fer-1 demonstrated superior protective effects against H2O2-induced oxidative damage in H9C2 cells compared to free Fer-1. In a model of acute MI in vivo, the PS-OD-Lipo@Fer-1 hydrogel significantly improved cardiac function, decreased apoptosis and fibrosis, and facilitated angiogenesis. These are achieved by efficiently and securely prolonging the duration of Fer-1 presence around the infarction area to mitigate ferroptosis in cardiomyocytes, ROS reduction and providing structural support with hydrogel after MI.