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可推广的锚定适体策略，用于将核酸治疗药物加载到外泌体上。

Generalizable anchor aptamer strategy for loading nucleic acid therapeutics on exosomes.

机构信息

State Key Laboratory of Experimental Hematology & The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics & International Joint Laboratory of Ocular Diseases (Ministry of Education), School of Medical Technology & School of Basic Medical Sciences, Tianjin Medical University, Qixiangtai Road, Heping District, 300070, Tianjin, China.

Public Laboratory & Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center & Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China.

出版信息

EMBO Mol Med. 2024 Apr;16(4):1027-1045. doi: 10.1038/s44321-024-00049-7. Epub 2024 Mar 6.

DOI:10.1038/s44321-024-00049-7
PMID:38448545
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11018858/
Abstract

Clinical deployment of oligonucleotides requires delivery technologies that improve stability, target tissue accumulation and cellular internalization. Exosomes show potential as ideal delivery vehicles. However, an affordable generalizable system for efficient loading of oligonucleotides on exosomes remain lacking. Here, we identified an Exosomal Anchor DNA Aptamer (EAA) via SELEX against exosomes immobilized with our proprietary CP05 peptides. EAA shows high binding affinity to different exosomes and enables efficient loading of nucleic acid drugs on exosomes. Serum stability of thrombin inhibitor NU172 was prolonged by exosome-loading, resulting in increased blood flow after injury in vivo. Importantly, Duchenne Muscular Dystrophy PMO can be readily loaded on exosomes via EAA (EXO). EXO elicited significantly greater muscle cell uptake, tissue accumulation and dystrophin expression than PMO in vitro and in vivo. Systemic administration of EXO elicited therapeutic levels of dystrophin restoration and functional improvements in mdx mice. Altogether, our study demonstrates that EAA enables efficient loading of different nucleic acid drugs on exosomes, thus providing an easy and generalizable strategy for loading nucleic acid therapeutics on exosomes.

摘要

寡核苷酸的临床应用需要改进稳定性、靶向组织积累和细胞内化的递送技术。外泌体作为理想的递药载体具有很大的应用潜力。然而，高效负载寡核苷酸到外泌体的经济实惠、通用型系统仍很缺乏。本研究通过针对固定化在我们专有的 CP05 肽上的外泌体的 SELEX 筛选，鉴定了一种外泌体锚定 DNA 适体（EAA）。EAA 与不同的外泌体具有高结合亲和力，并能够在外泌体上有效负载核酸药物。凝血酶抑制剂 NU172 的血清稳定性通过外泌体负载而延长，导致体内损伤后血流量增加。重要的是，通过 EAA（EXO）可以轻易地将杜氏肌营养不良症 PMO 加载到外泌体上。EXO 在体外和体内均比 PMO 引起更高的肌细胞摄取、组织积累和肌营养不良蛋白表达。EXO 的全身给药可引起 mdx 小鼠肌营养不良蛋白恢复的治疗水平和功能改善。总之，本研究表明，EAA 可实现不同核酸药物在外泌体上的高效装载，从而为核酸治疗药物在外泌体上的装载提供了一种简单、通用的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3698/11018858/089055398aa0/44321_2024_49_Fig10_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3698/11018858/fdd9a1b381b5/44321_2024_49_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3698/11018858/a4e541466bca/44321_2024_49_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3698/11018858/cc99f98706e9/44321_2024_49_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3698/11018858/7fc64d53d17d/44321_2024_49_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3698/11018858/38a99c02e322/44321_2024_49_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3698/11018858/a446a4e7fcf7/44321_2024_49_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3698/11018858/089055398aa0/44321_2024_49_Fig10_ESM.jpg

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