Abstract
Mesenchymal stem cell-derived extracellular vesicle (MSC-EV) is shown to promote cardiac repair, however, it still falls short in initiating myocardia proliferation restart. In this regard, ROS-induced DNA damage and responses are the culprit of cellcycle arrest. Here, this work constructs a hybrid cell-derived extracellular vesicle that is composed of MSC and macrophage membranes and encompasses MitoN, a ROS scavenger, to boost the healing of the heart. The MitoN, a NAD(P)H mimic, could target the mitochondrial to eliminate the ROS resuming the arrested cell cycle. The hybrid extracellular vesicle (N@MEV) could respond to the inflammatory signals generated during myocardial injury and thus enable superior targeting and enrichment to the location of the damage. L-arginine, which could be catalyzed by NOS and ROS into NO and SO provide a driving force, is immobilized within the vesicle (NA@MEV) to further enhance the N@MEV's potential to penetrate the cardiac stroma. In combination with multiple mechanisms, NA@MEV increased heart function 1.3-fold EF% versus MSC-EV in mouse myocardial injury model. A more in-depth mechanistic study found that the NA@MEV could modulate M2 macrophage; promote angiogenesis; reduce DNA damage and response, and thereby restart cardiomyocyte proliferation. Thus, this combined therapy shows synthetic effects in heart repair and regeneration.