Targeted delivery of platelet membrane modified extracellular vesicles into atherosclerotic plaque to regress atherosclerosis

•Platelet membrane modified extracellular vesicles (P-EVs) inherit the targeting ability towards injured endothelial cells which makes P-EVs accumulate in the plaques.•P-EVs are able to be endocytosed by inflammatory macrophages in plaques and transfer miRNAs into cytosol for further treatment. Atherosclerosis is a major underlying cause of cardiovascular disease. Although certain success has been achieved in treatment for atherosclerosis, the risk of cardiovascular diseases still remains high. Anti-inflammation therapy was proved to halt atherosclerosis progression, but their clinical application was hindered by the systemic immunosuppressive effect. Since macrophages play a key role in the development of atherosclerosis, targeted delivery of anti-inflammatory therapeutics to lesional macrophages might be an effective therapeutic strategy to resolve localized inflammation while reducing the adverse effects. Mesenchymal stem cells derived extracellular vesicles (MSC-EVs) are believed to possess anti-atherosclerosis effects by reducing inflammation. In this study, we fabricated platelet mimetic MSC-EVs (P-EVs) by decorating EVs with platelets membranes. P-EVs inherited the natural homing ability of platelets to plaques and therapeutic effects of MSC-EVs. When injected into atherosclerotic mice, P-EVs were recruited to injured endothelium, then penetrated into plaques followed with endocytosis by inflammatory macrophages through the interaction between platelet membranes proteins and macrophages surface proteins. Subsequently, P-EVs delivered miRNAs into the cytoplasm of macrophages through lysosomal escape, which attenuated the progression of atherosclerosis eventually by switching the macrophage into anti-inflammatory phenotype, scavenging the overproduced ROS and reducing lipid deposition in lesional macrophages. In general, our study demonstrated the pro-resolving potential of P-EVs for targeted anti-inflammation therapy of atherosclerosis.