Platelet membrane decorated exosomes enhance targeting efficacy and therapeutic index to alleviate arterial restenosis.

Rationale: Postinterventional restenosis is a major challenge in the treatment of peripheral vascular disease. Current anti-restenosis drugs inhibit neointima hyperplasia but simultaneously impair endothelial repair due to indiscrminative cytotoxity. Stem cell-derived exosomes provide multifaceted therapeutic effects by delivering functional miRNAs to endothelial cells, macrophages, and vascular smooth muscle cells (VSMCs). However, their clinical application is severly limited by poor targeting and low tissue uptake in injured vessel. Methods: To address this challenge, we constructed platelet-mimetic exosomes (PM-EXOs) by fusing mesenchymal stem cell (MSC)-derived exosomes with platelet membrane in order to harness the natural ability of platelets to target vascular injury, evade clearance by the mononuclear phagocyte system, and penetrate into the intima by hitchhiking on inflammatory monocytes. Results: PM-EXOs demonstrated enhanced cellular uptake by endothelial cells and macrophages, exerting proangiogenic and immunomodulatory effects via the delivery of functional miRNAs in vitro. The intravenously administrated PM-EXOs exhibited extended circulation time and a 4-fold enhancement in targeting injured arteries compared to unmodified exosomes. In mouse and rat carotid artery injury models, PM-EXOs were shown to promote endothelial repair on the denuded arterial wall, lower the M1/M2 ratio of infiltrated macrophages, and eventually inhibit phenotypic switch of vascular smooth muscle cells and reduce the formation of neointima without causing systemic toxicity. Conclusions: This biomimetic strategy may be leveraged to boost the therapeutic index of exosomes and realize the multifaceted treatment of arterial restenosis.