Platelet membrane and stem cell exosome hybrids enhance cellular uptake and targeting to heart injury

• Platelet membrane modification enhanced the accumulation of exosomes in injured tissues. • Platelet membrane substantially enhanced macropinocytosis-mediated cellular internalization of exosomes. • Platelet membrane hybrid improved the pharmacokinetic of stem cell derived exosomes. • This is a simple, fast, and translatable approach to modify therapeutic exosomes to make them disease targetable. We used platelet membrane to modify exosomes and rely on the natural “injury finding” ability of platelets to target the hybrid exosomes to vascular injury under myocardial infarction. Interestingly, we found that platelet membrane improved cellular binding and internalization of exosomes through enhanced macropinocytosis-mediated cellular internalization by endothelial cells and cardiomyocytes, but not by macrophages. Such modified exosomes showed improved targeting and functional benefits in vitro, and in a mouse myocardial infarction model in vivo, as compared to unmodified naive exosomes. Exosomes from mesenchymal stem cells have been widely studied as therapeutics to treat myocardial infarction. However, exosomes injected for therapeutic purposes face a number of challenges, including competition from endogenous exosomes, and the internalization/clearance by the mononuclear phagocyte system. There is also a lack of targeting. In this study, we hybridized stem cell-derived exosomes with platelet membranes to enhance their ability to target the injured heart and to reduce uptake by macrophages. Furthermore, we found that hybridization with platelet membranes induces macropinocytosis, enhancing the cellular uptake of exosomes by endothelial cells and cardiomyocytes drastically. In vivo studies showed the cardiac targeting ability of hybrid exosomes in a mouse model of myocardial infarction injury. Lastly, we determined cardiac functions and performed immunohistochemistry to confirm an enahnced therapeutic potency of platelet membrane modified exosomes as compared to non-modified exosomes. Our studies provide proof-of-concept data and a universal approach to enhance the binding and accumulation of exosomes in injured tissues.