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Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy

Author

Listed:
  • Yuqi Zhang

    (Soochow University)

  • Jinfeng Zhu

    (University of Rome Tor Vergata)

  • Ling Qiu

    (Jiangsu Institute of Nuclear Medicine)

  • Zhengzhong Lv

    (Soochow University)

  • Zhongsheng Zhao

    (Soochow University)

  • Xingxiang Ren

    (Soochow University)

  • Yirui Guo

    (Soochow University)

  • Yan Chen

    (Soochow University)

  • Miao Li

    (Soochow University)

  • Yurong Fan

    (The Second Affiliated Hospital of Soochow University)

  • Zhixin Han

    (Soochow University)

  • Yiming Feng

    (Soochow University)

  • Haibin Shi

    (Soochow University)

Abstract

RNA degradation using ribonuclease targeting chimeras (RiboTACs) is a promising approach for cancer therapy. However, potential off-target degradation is a serious issue. Here, a RiboTAC is designed for tumor microenvironment triggered activation. The tumor microenvironment activated RiboTAC (TaRiboTAC) incorporates two pre-miR-21 binders, a near-infrared fluorophore IR780, an RGD targeting peptide and a phenylboronic acid caged ribonuclease recruiter. The caged ribonuclease recruiter is embedded in the molecule and exposed in acidic pH, the phenylboronic acid cage is removed by H2O2 making the TaRiboTAC responsive to the acidic and high H2O2 levels in the tumor microenvironment. It is shown the TaRiboTAC targets tumor tissue and degrades pre-miR-21. The degradation of pre-miR-21 by TaRiboTACs significantly increases the radiotherapeutic susceptibility of cancer cells achieving efficient suppression of human lung adenocarcinoma A549 tumors in living mice.

Suggested Citation

  • Yuqi Zhang & Jinfeng Zhu & Ling Qiu & Zhengzhong Lv & Zhongsheng Zhao & Xingxiang Ren & Yirui Guo & Yan Chen & Miao Li & Yurong Fan & Zhixin Han & Yiming Feng & Haibin Shi, 2025. "Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56691-3
    DOI: 10.1038/s41467-025-56691-3
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    1. Yuquan Tong & Yeongju Lee & Xiaohui Liu & Jessica L. Childs-Disney & Blessy M. Suresh & Raphael I. Benhamou & Chunying Yang & Weimin Li & Matthew G. Costales & Hafeez S. Haniff & Sonja Sievers & Danie, 2023. "Programming inactive RNA-binding small molecules into bioactive degraders," Nature, Nature, vol. 618(7963), pages 169-179, June.
    2. Tracy S. Zimmermann & Amy C. H. Lee & Akin Akinc & Birgit Bramlage & David Bumcrot & Matthew N. Fedoruk & Jens Harborth & James A. Heyes & Lloyd B. Jeffs & Matthias John & Adam D. Judge & Kieu Lam & K, 2006. "RNAi-mediated gene silencing in non-human primates," Nature, Nature, vol. 441(7089), pages 111-114, May.
    3. Yuqi Zhang & Jing Fang & Shuyue Ye & Yan Zhao & Anna Wang & Qiulian Mao & Chaoxiang Cui & Yali Feng & Jiachen Li & Sunao Li & Mingyang Zhang & Haibin Shi, 2022. "A hydrogen sulphide-responsive and depleting nanoplatform for cancer photodynamic therapy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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