Ferrostatin-1-loaded polymeric micelles with IMTP modification and ROS responsiveness alleviate post-resuscitation myocardial dysfunction by inhibiting ferroptosis.

Post-resuscitation myocardial dysfunction (PRMD) is a leading cause of early mortality following cardiac arrest (CA), and ferroptosis has been implicated as a key mechanism. However, effective ferroptosis-targeted therapies are limited. Here, we developed ischemic myocardium-targeting peptide (IMTP)-modified, reactive oxygen species (ROS)-responsive polymeric micelles (Fer-1-NP) by encapsulating ferrostatin-1 (Fer-1) in poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) micelles and incorporating diselenide (Se-Se) bonds for ROS-triggered release and IMTP modification to promote cardiac localization. Fer-1-NP exhibited a uniform nanoscale morphology, high drug-loading efficiency, ROS-responsive release, and intrinsic ROS-scavenging activity. In vitro, Fer-1-NP protected H9c2 cardiomyocytes from hypoxia/reoxygenation injury by improving cell viability, restoring mitochondrial membrane potential, and reducing lipid peroxidation. In a rat CA model, Fer-1-NP exhibited increased cardiac fluorescence intensity, improved myocardial localization, enhanced left ventricular ejection fraction and mean arterial pressure, reduced serum cTnI and CK-MB levels, and preserved myocardial architecture compared with free Fer-1. Mechanistically, Fer-1-NP attenuated ferroptosis-associated changes by reducing myocardial Fe2+, 4-HNE, and MDA levels, restoring GSH levels, and regulating GPX4, ACSL4, SLC7A11, and FTH1 expression. In vivo imaging demonstrated the preferential cardiac accumulation of IMTP-modified micelles. These findings suggest that IMTP-functionalized, ROS-responsive Fer-1-NP provide cardioprotection against PRMD through modulation of ferroptosis-associated injury, representing a promising therapeutic strategy after cardiac arrest.