Biomimetic macrophage membrane-coated nanoparticles for targeted cardioprotection against myocardial ischaemia-reperfusion injury

Myocardial ischaemia-reperfusion injury (MIRI) exacerbates cardiomyocyte damage through oxidative stress, inflammation, and apoptosis, limiting the efficacy of reperfusion therapies. We developed PB1-Lip@M-CST, a biomimetic nanoparticle comprising procyanidin B1 (PB1)-loaded liposomes coated with macrophage cell membranes and surface-functionalized with the cardiac-specific targeting peptide CSTSMLKAC (CST). The nanoparticles were characterized for hydrodynamic size, zeta potential, core-shell morphology, retention of macrophage surface proteins (CCR2, CD11b, CD36), high encapsulation efficiency, and sustained drug release. In vitro, PB1-Lip@M-CST markedly reduced phagocytic uptake by RAW 264.7 macrophages, enhanced internalization in HL-1 cardiomyocytes in a CST-dependent manner, and provided superior protection in CoCl 2 -induced hypoxia-reoxygenation models by suppressing reactive oxygen species, lipid peroxidation, proinflammatory cytokines, and apoptosis. Mechanistic studies using CXCR4-overexpressing HL-1 cells and Plerixafor-treated cells confirmed that these effects were mediated via modulation of the CXCR4-associated PI3K/AKT1 signaling pathway and restoration of the BAX/BCL-2 balance. In a mouse model of MIRI, intravenous administration of PB1-Lip@M-CST prolonged systemic circulation, with markedly enhanced cardiac accumulation (highest heart AUC) and improved therapeutic index, reduced infarct size to 25.58 ± 2.96% (versus 49.22 ± 3.03% in the model group), preserved left ventricular ejection fraction at 50.42 ± 8.74%, attenuated serum injury biomarkers, and inhibited long-term fibrosis and apoptosis, with an excellent biosafety profile. These findings establish PB1-Lip@M-CST as a novel biomimetic platform that integrates macrophage membrane-mediated immune evasion with CST-directed cardiac homing to achieve cardiac-targeted delivery of PB1 and subsequent CXCR4-dependent modulation of the PI3K/AKT1 pathway in MIRI.