Reshaping cardiac microenvironments by macrophage-derived extracellular vesicles-coated Pd@CeO2 heterostructures for myocardial ischemia/reperfusion injury therapy

Abstract

Myocardial Ischemia/Reperfusion (MI/R) injury, a globally leading cause of mortality and disability, is commonly characterized by myriad inflammatory microenvironments, e.g. high level of reactive oxygen species (ROS), which has a high association with the consequent cell apoptosis and myocardial fibrosis. Herein, a reshaping strategy of cardiac microenvironments has been developed for relieving MI/R injury based on a biomimetic nanosystem (Pd@CeO2-M), which is composed of exterior macrophage-derived extracellular vesicles (MEVs) and encapsulated Pd@CeO2 heterostructures. Due to rapid electrons transfer on the interface, the Pd@CeO2 heterostructures exhibited outstanding ROS scavenging ability. The expression of Mac-1 and CD44 on the surface of Pd@CeO2-M contributes to adsorbing to the inflamed endothelium and efficient cellular uptake within damaged cardiac microenvironments, thus allowing for inflammation-targeting ability. In the mouse model of MI/R injury, Pd@CeO2-M accumulated and remained in the heart region over 24 hours. More importantly, Pd@CeO2-M regulated immune response and promoted anti-apoptotic and anti-inflammatory processes via upregulating the PI3K/Akt signaling pathway and inhibiting the TLR4/p38MAPK and TLR4/NF-κB signaling pathways, dissipated interstitial edema, triggered prominent angiogenesis, and ultimately improved cardiac function and ventricular remodeling. Overall, the Pd@CeO2-M heterostructures will provide an ideal paradigm of biomimetic nanomedicine confronting inflammatory diseases.