Gene Therapy with Enterovirus 3 C Protease: A Promising Strategy for Various Solid Tumors

Xiaotong Yang, Wei Li, Shaokang Yang, Zhuang Wang, Jiye Yin, Wenhao Zhang, Huimin Tao, Siqi Li, Xiaojia Guo, Qingsong Dai, Weiyan Zhu, Yuexiang Li, Xintong Yan, Chongda Luo, Jiazheng Li, Sichen Ren, Ping Wang, Yunfeng Shao, Yan Luo, Zhenyang Li, Jingjing Yang, Zhijie Chang, Ruiyuan Cao (), Song Li () and Wu Zhong ()
Additional contact information
Xiaotong Yang: Beijing Institute of Pharmacology and Toxicology
Wei Li: Beijing Institute of Pharmacology and Toxicology
Shaokang Yang: Beijing Institute of Pharmacology and Toxicology
Zhuang Wang: Beijing Institute of Pharmacology and Toxicology
Jiye Yin: Beijing Institute of Pharmacology and Toxicology
Wenhao Zhang: Beijing Institute of Pharmacology and Toxicology
Huimin Tao: Beijing Institute of Pharmacology and Toxicology
Siqi Li: Beijing Institute of Pharmacology and Toxicology
Xiaojia Guo: Beijing Institute of Pharmacology and Toxicology
Qingsong Dai: Beijing Institute of Pharmacology and Toxicology
Weiyan Zhu: Beijing Institute of Pharmacology and Toxicology
Yuexiang Li: Beijing Institute of Pharmacology and Toxicology
Xintong Yan: Beijing Institute of Pharmacology and Toxicology
Chongda Luo: Beijing Institute of Pharmacology and Toxicology
Jiazheng Li: Beijing Institute of Pharmacology and Toxicology
Sichen Ren: Beijing Institute of Pharmacology and Toxicology
Ping Wang: Beijing Institute of Pharmacology and Toxicology
Yunfeng Shao: Beijing Institute of Pharmacology and Toxicology
Yan Luo: Beijing Institute of Pharmacology and Toxicology
Zhenyang Li: Beijing Institute of Pharmacology and Toxicology
Jingjing Yang: Beijing Institute of Pharmacology and Toxicology
Zhijie Chang: Tsinghua University
Ruiyuan Cao: Beijing Institute of Pharmacology and Toxicology
Song Li: Beijing Institute of Pharmacology and Toxicology
Wu Zhong: Beijing Institute of Pharmacology and Toxicology

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

Abstract: Abstract Current cancer gene therapies rely primarily on antitumor immunity, but the exploration of alternative mRNA cargoes for direct antitumor effects is crucial to expand cancer gene therapies. Here we show that lipid nanoparticles (LNPs) carrying mRNA encoding a viral 3 C protease can efficiently suppress tumors by selectively inducing tumor cell apoptosis. In various solid tumor models, intracranial injection of LNPs carrying mRNA encoding the 3 C protease (3C-LNPs) significantly inhibits tumor growth and prolongs survival in glioblastoma models. Similarly, subcutaneous injection reduces tumor volume and inhibits angiogenesis in a breast cancer model, while intravenous injection inhibits tumor growth and angiogenesis and prolongs survival in hepatocellular carcinoma models. Mass spectrometry and cleavage site prediction assays identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as the main target degraded by the 3 C protease. This study suggests that viral protease mRNA could be a promising broad-spectrum antitumor therapeutic.

Date: 2025
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DOI: 10.1038/s41467-025-59440-8

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