Platelet Membrane Nanocarriers Cascade Targeting Delivery System to Improve Myocardial Remodeling Post Myocardial Ischemia–Reperfusion Injury

Abstract Although treatments for myocardial infarction have advanced significantly, the global mortality due to ischemia and subsequent reperfusion injury remains high. Here, a platelet (PLT) membrane nanocarrier (PL720) that encapsulates L‐arginine and FTY720 to facilitate the cascade‐targeted delivery of these substances to the myocardial injury site and enable the controlled release of L‐arginine and FTY720 is developed. Such an innovative approach shows enhanced cardioprotection through multiple target strategies involved in ischemia–reperfusion injury and late reperfusion inflammation. During the ischemia–reperfusion phase, PL720 targets and accumulates in damaged coronary arteries. PL720 rapidly releases L‐arginine, stimulating endothelial cells to produce NO, thereby dilating blood vessels and promoting blood flow recovery, while FTY720's sustained release exerts anti‐apoptotic effects. During the late reperfusion inflammatory phase, PL720 is captured by circulating inflammatory monocytes and transported into a deeper ischemic myocardial lesion. PL720 promotes macrophage polarization and accelerates the inflammatory repair. Furthermore, the issue of bradycardia associated with the clinical use of FTY720 is innovatively relieved. Therefore, PL720 is a vascular injury and inflammation dual targeting strategy, exhibiting significant potential for multi‐targeted therapy and clinical translation for cardiac injury.