Active and passive targeted delivery of anti-ferroptotic therapy for post-resuscitation myocardial dysfunction.

Post-resuscitation myocardial dysfunction (PRMD), associated with ferroptosis, contributes significantly to early mortality post-cardiopulmonary resuscitation. However, ferrostatin-1 (Fer-1), a ferroptosis inhibitor, faces challenges in clinical applicability for critical diseases. Here, we report a reactive oxygen species (ROS)-responsive (passively targeting ferroptosis) and myocardium-targeted drug delivery system that facilitates the on-demand delivery of nanoparticles (NPs) encapsulating a ferroptotic inhibitor as tested in a cardiac arrest model. Compared to ROSR@Fer-1 and free drugs, APTD@Fer-1 NPs exhibited good biocompatibility and significantly inhibited hypoxia-reoxygenation-induced ferroptosis in H9c2 cells. In rats, APTD @Fer-1 NPs improved PRMD, oxidative stress, inflammatory response, cardiac remodeling, and subsequent survival prognosis by inhibiting myocardial ferroptosis at 6 and 72 h after resuscitation. Importantly, APTD@Fer-1NPs allow for intravenous injections, emergency treatment, and single administration, offering a drug delivery strategy appropriate for critical care settings. These results offer insights that will facilitate further exploration of precision treatments for PRMD.