Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy
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 RiboTA...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56691-3 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yuqi Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4e45cf29d4a34ffe9701ade5887fa566 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-4e45cf29d4a34ffe9701ade5887fa5662025-02-09T12:46:18ZengNature PortfolioNature Communications2041-17232025-02-0116111510.1038/s41467-025-56691-3Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapyYuqi Zhang0Jinfeng Zhu1Ling Qiu2Zhengzhong Lv3Zhongsheng Zhao4Xingxiang Ren5Yirui Guo6Yan Chen7Miao Li8Yurong Fan9Zhixin Han10Yiming Feng11Haibin Shi12State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow UniversityDepartment of Experimental Medicine, TOR, University of Rome Tor VergataKey Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear MedicineState Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow UniversityState Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow UniversityState Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow UniversityState Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow UniversityState Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow UniversityState Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow UniversityDepartment of Radiology, The Second Affiliated Hospital of Soochow UniversityState Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow UniversityState Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow UniversityState Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, and Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow UniversityAbstract 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.https://doi.org/10.1038/s41467-025-56691-3 |
| spellingShingle | 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 Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy Nature Communications |
| title | Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy |
| title_full | Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy |
| title_fullStr | Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy |
| title_full_unstemmed | Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy |
| title_short | Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy |
| title_sort | stimulus activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy |
| url | https://doi.org/10.1038/s41467-025-56691-3 |
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