• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

治疗性寡核苷酸：改善内体运输的化学策略展望。

Therapeutic Oligonucleotides: An Outlook on Chemical Strategies to Improve Endosomal Trafficking.

机构信息

Oligonucleotide Discovery, Discovery Sciences Research and Development, AstraZeneca, 431 38 Gothenburg, Sweden.

Department of Laboratory Medicine, Clinical Research Centre, Karolinska Institute, 141 57 Stockholm, Sweden.

出版信息

Cells. 2023 Sep 11;12(18):2253. doi: 10.3390/cells12182253.

DOI:10.3390/cells12182253
PMID:37759475
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10527716/
Abstract

The potential of oligonucleotide therapeutics is undeniable as more than 15 drugs have been approved to treat various diseases in the liver, central nervous system (CNS), and muscles. However, achieving effective delivery of oligonucleotide therapeutics to specific tissues still remains a major challenge, limiting their widespread use. Chemical modifications play a crucial role to overcome biological barriers to enable efficient oligonucleotide delivery to the tissues/cells of interest. They provide oligonucleotide metabolic stability and confer favourable pharmacokinetic/pharmacodynamic properties. This review focuses on the various chemical approaches implicated in mitigating the delivery problem of oligonucleotides and their limitations. It highlights the importance of linkers in designing oligonucleotide conjugates and discusses their potential role in escaping the endosomal barrier, a bottleneck in the development of oligonucleotide therapeutics.

摘要

寡核苷酸疗法的潜力不可否认，已经有超过 15 种药物被批准用于治疗肝脏、中枢神经系统 (CNS) 和肌肉中的各种疾病。然而，将寡核苷酸疗法有效递送到特定组织仍然是一个主要挑战，限制了它们的广泛应用。化学修饰对于克服生物屏障以实现有效的寡核苷酸递送到感兴趣的组织/细胞至关重要。它们提供了寡核苷酸的代谢稳定性，并赋予了有利的药代动力学/药效学特性。本文综述了各种化学方法在减轻寡核苷酸递送问题及其局限性方面的作用。它强调了接头在设计寡核苷酸缀合物中的重要性，并讨论了它们在逃避内体屏障方面的潜在作用，内体屏障是寡核苷酸疗法发展的一个瓶颈。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/59a1d6b6d43f/cells-12-02253-g022.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/dcd4dc8f8ea2/cells-12-02253-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/426ae78c1a3c/cells-12-02253-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/bf894d982711/cells-12-02253-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/553504c354de/cells-12-02253-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/597a68829591/cells-12-02253-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/5f67859e8ff8/cells-12-02253-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/0f1a474c1f74/cells-12-02253-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/5b9e8b4e15fb/cells-12-02253-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/3f7ab46ecff0/cells-12-02253-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/6c8b4c394479/cells-12-02253-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/ad7d2a8f65e7/cells-12-02253-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/8c0fb677bc94/cells-12-02253-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/4180851ad9a4/cells-12-02253-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/30c53ff4b331/cells-12-02253-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/8500ccb0a023/cells-12-02253-g015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/faf2224e296c/cells-12-02253-g016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/c9229907e98f/cells-12-02253-g017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/7388df9a41ea/cells-12-02253-g018.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/edc9668d9ab8/cells-12-02253-g019.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/5638efb45f58/cells-12-02253-g020.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/8c2330d7564c/cells-12-02253-g021.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/59a1d6b6d43f/cells-12-02253-g022.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/dcd4dc8f8ea2/cells-12-02253-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/426ae78c1a3c/cells-12-02253-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/bf894d982711/cells-12-02253-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/553504c354de/cells-12-02253-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/597a68829591/cells-12-02253-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/5f67859e8ff8/cells-12-02253-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/0f1a474c1f74/cells-12-02253-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/5b9e8b4e15fb/cells-12-02253-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/3f7ab46ecff0/cells-12-02253-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/6c8b4c394479/cells-12-02253-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/ad7d2a8f65e7/cells-12-02253-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/8c0fb677bc94/cells-12-02253-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/4180851ad9a4/cells-12-02253-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/30c53ff4b331/cells-12-02253-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/8500ccb0a023/cells-12-02253-g015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/faf2224e296c/cells-12-02253-g016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/c9229907e98f/cells-12-02253-g017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/7388df9a41ea/cells-12-02253-g018.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/edc9668d9ab8/cells-12-02253-g019.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/5638efb45f58/cells-12-02253-g020.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/8c2330d7564c/cells-12-02253-g021.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e41/10527716/59a1d6b6d43f/cells-12-02253-g022.jpg

相似文献

1
Therapeutic Oligonucleotides: An Outlook on Chemical Strategies to Improve Endosomal Trafficking.治疗性寡核苷酸：改善内体运输的化学策略展望。
Cells. 2023 Sep 11;12(18):2253. doi: 10.3390/cells12182253.
2
Hyaluronan-based delivery of therapeutic oligonucleotides for treatment of human diseases.基于透明质酸的治疗性寡核苷酸递药系统治疗人类疾病。
Expert Opin Drug Deliv. 2019 Jun;16(6):621-637. doi: 10.1080/17425247.2019.1617693. Epub 2019 May 20.
3
Chemical Manipulation of the Endosome Trafficking Machinery: Implications for Oligonucleotide Delivery.内体运输机制的化学调控：对寡核苷酸递送的影响
Biomedicines. 2021 May 5;9(5):512. doi: 10.3390/biomedicines9050512.
4
Endosomal escape cell-penetrating peptides significantly enhance pharmacological effectiveness and CNS activity of systemically administered antisense oligonucleotides.内体逃逸细胞穿透肽显著提高了系统给予的反义寡核苷酸的药理学效力和中枢神经系统活性。
Int J Pharm. 2021 Apr 15;599:120398. doi: 10.1016/j.ijpharm.2021.120398. Epub 2021 Feb 26.
5
Site Selective Antibody-Oligonucleotide Conjugation via Microbial Transglutaminase.通过微生物转谷氨酰胺酶实现抗体-寡核苷酸的定点偶联。
Molecules. 2019 Sep 10;24(18):3287. doi: 10.3390/molecules24183287.
6
Simultaneous inhibition of endocytic recycling and lysosomal fusion sensitizes cells and tissues to oligonucleotide therapeutics.同时抑制内吞循环和溶酶体融合可增强细胞和组织对寡核苷酸治疗药物的敏感性。
Nucleic Acids Res. 2023 Feb 28;51(4):1583-1599. doi: 10.1093/nar/gkad023.
7
Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?RNA 治疗药物的内体逃逸：我们如何解决这个限速问题？
RNA. 2023 Apr;29(4):396-401. doi: 10.1261/rna.079507.122. Epub 2023 Jan 20.
8
Delivery of RNA Therapeutics: The Great Endosomal Escape!RNA 治疗药物的递送：伟大的内体逃逸！
Nucleic Acid Ther. 2022 Oct;32(5):361-368. doi: 10.1089/nat.2022.0004. Epub 2022 May 24.
9
The delivery of therapeutic oligonucleotides.治疗性寡核苷酸的递送
Nucleic Acids Res. 2016 Aug 19;44(14):6518-48. doi: 10.1093/nar/gkw236. Epub 2016 Apr 15.
10
Delivery of Oligonucleotide Therapeutics: Chemical Modifications, Lipid Nanoparticles, and Extracellular Vesicles.寡核苷酸治疗药物的递送：化学修饰、脂质纳米粒和细胞外囊泡。
ACS Nano. 2021 Sep 28;15(9):13993-14021. doi: 10.1021/acsnano.1c05099. Epub 2021 Sep 10.

引用本文的文献

1
Targeted Delivery of miR-34a via Anti-CD47 Antibody Conjugates for Enhanced Cancer Immunotherapy in Triple Negative Breast Cancer.通过抗CD47抗体偶联物靶向递送miR-34a以增强三阴性乳腺癌的癌症免疫治疗
Small. 2025 Sep;21(36):e04468. doi: 10.1002/smll.202504468. Epub 2025 Jul 22.
2
Aptamer-ODN Chimeras: Enabling Cell-Specific ODN Targeting Therapy.适体-寡核苷酸嵌合体：实现细胞特异性寡核苷酸靶向治疗。
Cells. 2025 May 12;14(10):697. doi: 10.3390/cells14100697.
3
Linker Design Principles for the Precision Targeting of Oncogenic G-Quadruplex DNA with G4-Ligand-Conjugated Oligonucleotides.

本文引用的文献

1
Targeted tissue delivery of RNA therapeutics using antibody-oligonucleotide conjugates (AOCs).利用抗体-寡核苷酸缀合物（AOCs）实现 RNA 治疗药物的靶向组织递送。
Nucleic Acids Res. 2023 Jul 7;51(12):5901-5910. doi: 10.1093/nar/gkad415.
2
Enhancing the Effectiveness of Oligonucleotide Therapeutics Using Cell-Penetrating Peptide Conjugation, Chemical Modification, and Carrier-Based Delivery Strategies.通过细胞穿透肽偶联、化学修饰和基于载体的递送策略提高寡核苷酸疗法的有效性
Pharmaceutics. 2023 Apr 3;15(4):1130. doi: 10.3390/pharmaceutics15041130.
3
Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection.
用于通过G4配体偶联寡核苷酸精准靶向致癌G-四链体DNA的连接子设计原则
Bioconjug Chem. 2025 Apr 16;36(4):724-736. doi: 10.1021/acs.bioconjchem.5c00008. Epub 2025 Mar 20.
4
Nanobody-Oligonucleotide Conjugates (NucleoBodies): The Next Frontier in Oligonucleotide Therapy.纳米抗体-寡核苷酸缀合物（核小体）：寡核苷酸疗法的新前沿。
Pharm Res. 2025 Feb;42(2):219-236. doi: 10.1007/s11095-025-03829-z. Epub 2025 Feb 15.
5
Evolution of antisense oligonucleotides: navigating nucleic acid chemistry and delivery challenges.反义寡核苷酸的发展：应对核酸化学及递送挑战
Expert Opin Drug Discov. 2025 Jan;20(1):63-80. doi: 10.1080/17460441.2024.2440095. Epub 2024 Dec 17.
6
Thiol-Specific Linkers for the Synthesis of Oligonucleotide Conjugates via Metal-Free Thiol-Ene Click Reaction.用于通过无金属硫醇-烯点击反应合成寡核苷酸缀合物的硫醇特异性连接子。
Bioconjug Chem. 2024 Sep 12;35(10):1553-67. doi: 10.1021/acs.bioconjchem.4c00336.
二价 siRNA 在肺部具有生物利用度，并能有效阻止 SARS-CoV-2 感染。
Proc Natl Acad Sci U S A. 2023 Mar 14;120(11):e2219523120. doi: 10.1073/pnas.2219523120. Epub 2023 Mar 9.
4
Chemical Biology Approaches toward Precise Structure Control of IgG-Based Antibody-Oligonucleotide Conjugates.基于化学生物学的方法实现 IgG 型抗体-寡核苷酸偶联物的精确结构控制。
Chembiochem. 2023 May 2;24(9):e202300077. doi: 10.1002/cbic.202300077. Epub 2023 Mar 30.
5
Chemistry, structure and function of approved oligonucleotide therapeutics.已获批的寡核苷酸治疗药物的化学、结构和功能。
Nucleic Acids Res. 2023 Apr 11;51(6):2529-2573. doi: 10.1093/nar/gkad067.
6
Drug Discovery Perspectives of Antisense Oligonucleotides.反义寡核苷酸的药物发现前景
Biomol Ther (Seoul). 2023 May 1;31(3):241-252. doi: 10.4062/biomolther.2023.001. Epub 2023 Mar 2.
7
A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future.基于蛋白质和肽的化学偶联物综述：过去、现在与未来
Pharmaceutics. 2023 Feb 10;15(2):600. doi: 10.3390/pharmaceutics15020600.
8
Convenient Solid-Phase Attachment of Small-Molecule Ligands to Oligonucleotides via a Biodegradable Acid-Labile P-N-Bond.通过可生物降解的酸不稳定 P-N 键将小分子配体方便地连接到寡核苷酸上。
Molecules. 2023 Feb 16;28(4):1904. doi: 10.3390/molecules28041904.
9
Dual-responsive bioconjugates bearing a bifunctional adaptor for robust cytosolic peptide delivery.具有双功能接头的双响应型生物缀合物，用于稳健的细胞溶质肽传递。
J Control Release. 2023 Mar;355:675-684. doi: 10.1016/j.jconrel.2023.02.014. Epub 2023 Feb 17.
10
Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?RNA 治疗药物的内体逃逸：我们如何解决这个限速问题？
RNA. 2023 Apr;29(4):396-401. doi: 10.1261/rna.079507.122. Epub 2023 Jan 20.