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Immune regulation therapies have been considered promising in the treatment of myocardial ischemia reperfusion (MI/R) injury. Mesenchymal stem cells derived extracellular vesicles (MSC-EVs) are of great potential for immune modulation by reprogramming macrophages but their therapeutic efficacy is hindered by insufficient targeting ability in vivo. Herein, we introduced the platelet membrane modified EVs (P-EVs) based on membrane fusion method to mimic the binding ability of platelets to monocytes. In the mouse model of MI/R injury, the intravenously injected P-EVs were mainly carried by circulating monocytes into the ischemic myocardium. In the inflammatory microenvironment, those monocytes subsequently differentiated into macrophages with enhanced phagocytosis, which probably promoted in-situ endocytosis of the superficial P-EVs by monocytes differentiated macrophages in large quantities. Then, the P-EVs successfully escaped from the macrophage lysosome and released the functional microRNAs (miRNAs) into the cytosol which facilitated the inflammatory macrophages (M1 phenotype) reprogramming to reparative macrophages (M2 phenotype). Finally, the immune microenvironment was regulated to realize cardiac repair. Thus, we supposed that the most likely delivery method was that monocytes mediated P-EVs migration into ischemic myocardium where P-EVs were mainly in-situ endocytosed by monocytes derived macrophages, which holds potential for immunoregulation on MI/R and other immune-related diseases in the future., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Stem cell-derived extracellular vesicles (EVs) have been demonstrated to be effective in heart repair and regeneration post infarction. However, the poor homing efficiency and low yields of these therapeutics remain the major obstacles before they can be used in the clinic. To improve the delivery efficiency of EVs to ischemia-injured myocardium, we modified mesenchymal stem cell (MSC)-derived EVs with monocyte mimics through the method of membrane fusion. Monocyte mimic-bioinspired MSC-EVs (Mon-Exos) exhibited enhanced targeting efficiency to injured myocardium by mimicking the recruitment feature of monocytes after MI/RI, thus contributing to these exclusive adhesive molecules on monocyte mimics, particularly the Mac1/LFA1-ICAM-1 interaction. Through this strategy, Mon-Exos were shown to promote endothelial maturation during angiogenesis and modulate macrophage subpopulations after MI/RI, consistent with MSC-Exos biofunctions, and eventually improve therapeutic outcomes in cardiac function and pathohistology changes after treatments in a mouse MI/RI model. Ultimately, this strategy might provide us with a better way to assess the effects of stem cell EVs and offer additional techniques to help clinicians better manage regenerative therapeutics for ischemic heart diseases., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

• 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. [ABSTRACT FROM AUTHOR]