Platelet Membrane‐Fused Circulating Extracellular Vesicles Protect the Heart from Ischemia/Reperfusion Injury

Abstract Myocardial ischemia/reperfusion injury (I/RI) may potentiate cardiac remodeling and heart failure, while effective therapies for I/RI remain lacking. Circulating human plasma‐derived extracellular vesicles (hEV) have great potential to protect against I/RI. However, the effective delivery of hEV in vivo remains a limiting factor for clinical application. The present study constructs a biomimetic delivery system of platelet membrane‐fused hEV (P‐hEV), utilizing the natural affinity of platelets for hEV delivery to the injured vascular and myocardial sites. The results show that platelet membrane and hEV membrane fusion can be achieved through repeated extrusion. Compared to non‐modified hEV, P‐hEV uptake is greatly enhanced in human umbilical vein endothelial cells (HUVECs) stressed by oxygen‐glucose deprivation/reperfusion (OGD/R). Functionally, P‐hEV inhibits HUVEC and neonatal rat cardiomyocyte (NRCM) apoptosis and promotes HUVECs migration and tube formation under OGD/R stress in vitro. Intravenous delivery of P‐hEV more effectively targets and accumulates at injury sites in the heart. Furthermore, P‐hEV significantly enhances protection against acute I/RI and attenuates cardiac remodeling at three weeks post‐I/RI. In conclusion, the platelet membrane‐fused hEV delivery system enhances the target delivery of EV to protect against myocardial I/RI, presenting a novel drug delivery system for ischemic heart diseases.