A therapeutic relay strategy enabled by spatiotemporally programmable nanoplatforms for multilayered cardioprotection against MI/RI

Myocardial ischemia/reperfusion injury (MI/RI) is driven by a cascade of pathological events, including oxidative stress and the activation of novel cell death pathways such as ferroptosis. The stage-specific shift in dominant cell death modalities coupled with the inherently low bioavailability of conventional therapeutics in the rhythmically contracting heart critically constrain the efficacy of single-target interventions. Here, we developed a spatiotemporally controllable “therapeutic relay” strategy based on a metal–phenolic network-hybridized liposomal system (MP@T NPs). During the early reperfusion phase, the tannic acid–cerium (TA–Ce) network shell exhibits reactive oxygen species (ROS) scavenging and anti-inflammatory activities, thereby effectively mitigating apoptosis and autophagy-associated cell death. Concurrently, its high affinity for collagen ensures the prolonged and targeted retention of the nanoparticles at the injury site. Upon the initiation of ferroptosis, ultrasound (US) irradiation subsequently induces the phase transition and vaporization of perfluoropentane (PFP), triggering the on-demand release of the arachidonate lipoxygenase (ALOX) inhibitor ML351 to precisely suppress ferroptotic cell death. This sequential action inhibits ferroptosis by downregulating ACSL4 and upregulating GPX4, thereby attenuating lipid peroxidation and restoring mitochondrial function in H9c2 cells. In the MI/RI rat model, MP@T NPs reduced ROS levels and iron deposition, suppressed inflammation, and restored the ejection fraction and fractional shortening. This novel, noninvasively regulated therapeutic platform enables temporally precise intervention in the key pathological cascades of MI/RI, offering a promising multitarget approach for enhancing myocardial salvage and functional recovery.