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

Yuqi Zhang, Jinfeng Zhu, Ling Qiu, Zhengzhong Lv, Zhongsheng Zhao, Xingxiang Ren, Yirui Guo, Yan Chen, Miao Li, Yurong Fan, Zhixin Han, Yiming Feng and Haibin Shi ()
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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

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56691-3

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