Platelet membrane-fused and cardiac homing peptide-modified liposomes deliver puerarin to attenuate myocardial ischemia/reperfusion injury by inhibiting pyroptosis.

To address the critical role of oxidative stress-mediated pyroptosis in myocardial ischemia-reperfusion injury (MI/RI), we developed a novel biomimetic drug delivery system-platelet membrane-fused and cardiac homing peptide-modified liposomes (PUE@CHP/PM-L) which were designed to overcome the clinical limitation of poor myocardial targeting of puerarin (PUE). Fluorescence detection analysis demonstrated that platelet membrane (PM) modification endowed the liposomes with both immune evasion capability and targeting specificity toward ischemic myocardial vasculature, while the cardiac homing peptide (CHP) mediated specific uptake by ischemic cardiomyocytes. Cellular experiments revealed that PUE@CHP/PM-L effectively suppressed NLRP3 inflammasome activation by scavenging ROS, thereby downregulating Caspase-1 activity and GSDMD cleavage, and significantly reducing hypoxia/reoxygenation-induced cardiomyocyte pyroptosis. In vivo imaging confirmed that DiR@CHP/PM-L enhanced drug targeting and retention in ischemic myocardium while markedly reducing hepatic and splenic sequestration. Pharmacological animal studies demonstrated that PUE@CHP/PM-L significantly reduced infarct size, upregulated Connexin 43 expression, improved cardiac function and attenuated myocardial fibrosis by inhibiting the NLRP3/Caspase-1/GSDMD signaling pathway. By employing a synergistic targeting strategy, this study successfully overcame the delivery limitations of PUE, enabling the drug to fully exert its pyroptosis-inhibiting effects within ischemic cardiomyocytes, thereby providing a novel approach for the precise treatment of MI/RI.