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一种用于增强小细胞外囊泡向具有酸性微环境的疾病区域富集的pH响应性聚乙二醇包被策略。

A pH-responsive PEG coating strategy for enhancing the enrichment of small extracellular vesicles towards disease regions with acidic microenvironment.

作者信息

Zhao Jianwei, Niu Xinyu, Luo Lei, Yuan Ji, Zhang Juntao, Niu Xin, Tian Hengli, Yang Yunlong, Deng Zhifeng, Wang Yang

机构信息

Department of Neurosurgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China.

School of Biomedical Engineering, Shanghai Jiao Tong University, No. 1954 Huashan Road, Shanghai, 200030, China.

出版信息

Mater Today Bio. 2025 May 17;32:101878. doi: 10.1016/j.mtbio.2025.101878. eCollection 2025 Jun.

DOI:10.1016/j.mtbio.2025.101878
PMID:40520558
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12166399/
Abstract

The clinical translation of small extracellular vesicles (sEVs) as nanocarriers and therapeutic agents is severely hindered by their rapid clearance, leading to significant off-target effects. Polyethylene glycol (PEG) coating of sEVs provides a straightforward approach to address this challenge, yet it compromises their cellular internalization. To overcome this issue, we developed an acid-responsive PEG coating strategy for sEVs using 2,5-dihydroxy-4-methyl-2,5-dioxo-3-furanpropanoic acid (CDM)-modified methoxy PEG (mPEG-CDM). Western blot analysis and cellular uptake studies demonstrated that mPEG-CDM anchors to sEV membrane proteins through acid-labile cis-aconityl bonds, significantly reducing macrophage-mediated phagocytosis under physiological conditions, while restoring cellular internalization in endothelial cells (bEnd.3) and tumor cells (GL261) under weakly acidic conditions. imaging revealed that mPEG-CDM-modified sEVs, derived from glioma cells (GsEVs) and induced pluripotent stem cells (IsEVs), selectively accumulated in glioma tumor sites and ischemic brain regions in orthotopic glioma and stroke mouse models, respectively. Furthermore, studies demonstrated enhanced anti-tumor efficacy of GsEVs as drug carriers for glioma therapy and improved angiogenesis in ischemic stroke using IsEVs. Overall, this pH-responsive PEG coating strategy provides an effective approach for passive enrichment and offers valuable guidance for the design of surface-engineered sEVs in disease therapy.

摘要

小细胞外囊泡（sEVs）作为纳米载体和治疗剂的临床转化受到其快速清除的严重阻碍，导致显著的脱靶效应。sEVs的聚乙二醇（PEG）包被提供了一种直接的方法来应对这一挑战，但它会损害其细胞内化。为了克服这个问题，我们开发了一种使用2,5-二羟基-4-甲基-2,5-二氧代-3-呋喃丙酸（CDM）修饰的甲氧基PEG（mPEG-CDM）对sEVs进行酸响应性PEG包被的策略。蛋白质免疫印迹分析和细胞摄取研究表明，mPEG-CDM通过酸不稳定的顺乌头酰键锚定在sEV膜蛋白上，在生理条件下显著减少巨噬细胞介导的吞噬作用，同时在弱酸性条件下恢复内皮细胞（bEnd.3）和肿瘤细胞（GL261）中的细胞内化。成像显示，源自胶质瘤细胞（GsEVs）和诱导多能干细胞（IsEVs）的mPEG-CDM修饰的sEVs分别在原位胶质瘤和中风小鼠模型的胶质瘤肿瘤部位和缺血性脑区域选择性积累。此外，研究表明，GsEVs作为胶质瘤治疗的药物载体具有增强的抗肿瘤疗效，并且使用IsEVs可改善缺血性中风中的血管生成。总体而言，这种pH响应性PEG包被策略为被动富集提供了一种有效方法，并为疾病治疗中表面工程化sEVs的设计提供了有价值的指导。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/8332f36264e3/mmcfigs12.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/374d9e4a8712/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/be1ce7053f32/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/4a0d45a02016/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/287618163fb5/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/abb5fcc86d17/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/dd717f5165d7/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/5d5710f78ee7/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/a878087b7fcf/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/ad1ab75778eb/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/c32828b43257/mmcfigs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/ea4771903179/mmcfigs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/f625aca2d510/mmcfigs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/653028cc7f78/mmcfigs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/7171b739f9ae/mmcfigs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/2e36d80cf818/mmcfigs6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/1eb40f81cf45/mmcfigs7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/654f60fac50a/mmcfigs8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/518d6992b617/mmcfigs9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/bf860d6fd6fc/mmcfigs10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/62b0641a71d0/mmcfigs11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e920/12166399/8332f36264e3/mmcfigs12.jpg

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