Precisely co-delivery of protein and ROS scavenger with platesomes for enhanced endothelial barrier preservation against myocardial ischemia reperfusion injury

Abstract

Following myocardial ischemia–reperfusion (MI/R), the endothelial barrier is heavily damaged. This is partially due to the accumulation of intracellular reactive oxygen species (ROS) in endothelial cells, leading to disruptive intercellular VE-Cadherin junctions and endothelial cells apoptosis. Systemic administration of drugs is limited by poor delivery and release at pathological sites, resulting in compromised therapeutic effect. Herein, by exploiting the inherent nature of platelets migrating to injured endothelium and local activation of thrombin, we fabricated functional platesomes (Fe@PLP-TR-A) to co-deliver angiopoietin-like 4 (ANGPTL4) and ROS scavenger Fe3O4 to injured endothelium in heart affected by MI/R. Thanks to the capability for multidrug loading and easy-modification feature of platesomes, we conjugated ANGPTL4 on the surface of platesomes with a thrombin responsive peptide and encapsulated Fe3O4 in the inner space. After systemic injection, Fe@PLP-TR-A successfully arrived at the endothelial cells at injured endothelium due to the platelet-mimetic adhesion effect of platesomes which was fabricated by fusing platelet membranes and lipid membranes. Following the cleavage of thrombin-responsive peptide, which was activated by injured endothelium, ANGPTL4 was released extracellularly and bound to the receptor on endothelial cells to prevent the disruption of VE-Cadherin junctions. Further, endo-lysosomal escape of Fe3O4 to cytosol exerted ROS scavenging effect and protected endothelial cells from apoptosis. VE-Cadherin maintenance and cell rescue together preserved the endothelial barrier and subsequently decreased leukocytes extravasation and intracardial hemorrhage, alleviated cardiomyocyte apoptosis and eventually improved cardiac function. This work demonstrates a practical platform for the treatment of reperfusion injury by enhancing targeted release of drugs to injured endothelium.