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Bioorthogonal Reaction-Mediated Tumor-Selective Delivery of CRISPR/Cas9 System for Dual-Targeted Cancer Immunotherapy |
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| Authors: | Prof Jingjing Yang Dr Kaiyong Yang Shiyu Du Wen Luo Prof Chao Wang Dr Hongmei Liu Kunguo Liu Zhibin Zhang Dr Yanfeng Gao Prof Xin Han Prof Yujun Song |
| Institution: | 1. Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing, 210023 China
College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Xianlin Road 163, Nanjing, 210023 China These authors contributed equally to this work.;2. Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing, 210023 China These authors contributed equally to this work.;3. Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Xianlin Road 138, Nanjing, 210023 China;4. College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Xianlin Road 163, Nanjing, 210023 China;5. School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, 225002 China;6. Academy of National Food and Strategic Reserves Administration, No. 11 Baiwanzhuang Str, Xicheng District, Beijing, 100037 China |
| Abstract: | CRISPR system-assisted immunotherapy is an attractive option in cancer therapy. However, its efficacy is still less than expected due to the limitations in delivering the CRISPR system to target cancer cells. Here, we report a new CRISPR/Cas9 tumor-targeting delivery strategy based on bioorthogonal reactions for dual-targeted cancer immunotherapy. First, selective in vivo metabolic labeling of cancer and activation of the cGAS-STING pathway was achieved simultaneously through tumor microenvironment (TME)-biodegradable hollow manganese dioxide (H-MnO2) nano-platform. Subsequently, CRISPR/Cas9 system-loaded liposome was accumulated within the modified tumor tissue through in vivo click chemistry, resulting in the loss of protein tyrosine phosphatase N2 (PTPN2) and further sensitizing tumors to immunotherapy. Overall, our strategy provides a modular platform for precise gene editing in vivo and exhibits potent antitumor response by boosting innate and adaptive antitumor immunity. |
| Keywords: | cGAS/STING Pathway CRISPR/Cas Gene Editing Immunotherapy Ptpn2 Deletion |