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

IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-01-01 DOI:10.7150/thno.103747
Shan Lu, Ruihan Wang, Minghao Cai, Chen Yuan, Bin Gao, Daqiao Guo, Yisheng Xu, Weiguo Fu, Xiaohua Yu, Yi Si
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Abstract

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.

血小板膜修饰外泌体可提高动脉再狭窄的靶向疗效和治疗指标。
理由:介入后再狭窄是周围血管疾病治疗的主要挑战。目前的抗再狭窄药物抑制新内膜增生,但同时由于不加区分的细胞毒性而损害内皮修复。干细胞来源的外泌体通过向内皮细胞、巨噬细胞和血管平滑肌细胞(VSMCs)传递功能性mirna,提供多方面的治疗效果。然而,它们的临床应用受到损伤血管靶向性差和组织摄取低的严重限制。方法:为了解决这一挑战,我们将间充质干细胞(MSC)衍生的外泌体与血小板膜融合,构建了模拟血小板外泌体(PM-EXOs),以利用血小板靶向血管损伤的天然能力,逃避单核吞噬细胞系统的清除,并通过搭车炎性单核细胞进入内膜。结果:PM-EXOs增强了内皮细胞和巨噬细胞的细胞摄取,通过在体外传递功能性mirna发挥促血管生成和免疫调节作用。与未修饰的外泌体相比,静脉给药的pm - exo表现出延长的循环时间和靶向损伤动脉的4倍增强。在小鼠和大鼠颈动脉损伤模型中,pm - exo可促进脱落动脉壁内皮修复,降低浸润巨噬细胞的M1/M2比值,最终抑制血管平滑肌细胞的表型转换,减少新生内膜的形成,而不引起全身毒性。结论:利用这种仿生策略可以提高外泌体的治疗指数,实现动脉再狭窄的多方面治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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