Tumor-microenvironment activated duplex genome-editing nanoprodrug for sensitized near-infrared titania phototherapy  

作　　者：Zekun Li Yongchun Pan Shiyu Du Yayao Li Chao Chen Hongxiu Song Yueyao Wu Xiaowei Luan Qin Xu Xiaoxiang Guan Yujun Song Xin Han 

机构地区：[1]Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica,School of Medicine&Holistic Integrative Medicine,Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China [2]College of Engineering and Applied Sciences,Jiangsu Key Laboratory of Artificial Functional Materials,State Key Laboratory of Analytical Chemistry for Life Science,Nanjing University,Najing 210023,China [3]Department of Oncology,The First Affiliated Hospital of Nanjing Medical University,Nanjing 210029,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第11期4224-4234,共11页药学学报（英文版）

基　　金：supported by the National Key R&D Program of China (2019YFA0709200);the financial support from the National Natural Science Foundation of China (21874066, 81601632, and 31901010);the Natural Science Foundation of Jiangsu Province(BK20160616, China);the Fundamental Research Funds for Central Universities;the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine, China);the Key International Cooperation of the National Natural Science Foundation of China (No.81920108029);the Key Foundation for Social Development Project of the Jiangsu Province,China (BE2021741);Jiangsu Specially Appointed Professorship Foundation (China)

摘　　要：Near-infrared(NIR)-light-triggered nanomedicine, including photodynamic therapy(PDT)and photothermal therapy(PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability and minimal invasion, but the tumor eradication is limited by the intrinsic anti-stress response of tumor cells. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on oxygen-deficient titania(TiO_(2-x)) for mild NIR-phototherapy. In tumor microenvironment, the overexpressed hyaluronidase(HAase) and glutathione(GSH) can readily destroy hyaluronic acid(HA) and disulfide bond and releases the Cas9/sgRNA from TiO_(2-x) to target the stress alleviating regulators, i.e., nuclear factor E2-related factor 2(NRF2) and heat shock protein 90a(HSP90a), thereby reducing the stress tolerance of tumor cells. Under subsequent NIR light illumination, the TiO_(2-x) demonstrates a higher anticancer effect both in vitro and in vivo. This strategy not only provides a promising modality to kills cancer cells in a minimal side-effects manner by interrupting anti-stress pathways but also proposes a general approach to achieve controllable gene editing in tumor region without unwanted genetic mutation in normal environments.

关 键 词：Near infrared phototherapy Gene editing Nuclear factor E2-related factor 2 .Heat shock protein 90c TiO_(2-x) Sensitized phototherapy Nanoprodrug Tumor microenvironment 

分 类 号：R730.5[医药卫生—肿瘤]