Decomposable Nanoagonists Enable NIR-Elicited cGAS-STING Activation for Tandem-Amplified Photodynamic-Metalloimmunotherapy

作者全名："Guo, Xun; Tu, Peng; Wang, Xiaoting; Du, Chier; Jiang, Weixi; Qiu, Xiaoling; Wang, Jingxue; Chen, Liang; Chen, Yu; Ren, Jianli"

作者地址："[Guo, Xun; Wang, Xiaoting; Du, Chier; Jiang, Weixi; Wang, Jingxue; Ren, Jianli] Chongqing Med Univ, Affiliated Hosp 2, Ultrasound Dept, Chongqing Key Lab Ultrasound Mol Imaging, Chongqing 400010, Peoples R China; [Tu, Peng] Chongqing Med Univ, Women & Childrens Hosp, Chongqing Hlth Ctr Women & Children, Dept Ultrasound, Chongqing 401147, Peoples R China; [Qiu, Xiaoling] Chongqing Med Univ, Affiliated Hosp 2, Dept Intens Care Unit, Chongqing 400010, Peoples R China; [Chen, Liang; Chen, Yu] Shanghai Univ, Sch Life Sci, Materdicine Lab, Shanghai 200444, Peoples R China; [Chen, Yu] Shanghai Univ, Wenzhou Inst, Oujiang Lab, Zhejiang Lab Regenerat Med Vis & Brain Hlth, Wenzhou 325088, Zhejiang, Peoples R China; [Chen, Yu] Shanghai Inst Materdicine, Shanghai 200051, Peoples R China"

通信作者："Ren, JL (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Ultrasound Dept, Chongqing Key Lab Ultrasound Mol Imaging, Chongqing 400010, Peoples R China.; Chen, L; Chen, Y (通讯作者)，Shanghai Univ, Sch Life Sci, Materdicine Lab, Shanghai 200444, Peoples R China.; Chen, Y (通讯作者)，Shanghai Univ, Wenzhou Inst, Oujiang Lab, Zhejiang Lab Regenerat Med Vis & Brain Hlth, Wenzhou 325088, Zhejiang, Peoples R China.; Chen, Y (通讯作者)，Shanghai Inst Materdicine, Shanghai 200051, Peoples R China."

来源：ADVANCED MATERIALS

ESI学科分类：MATERIALS SCIENCE

WOS号：WOS:001169784700001

JCR分区：Q1

影响因子：27.4

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：cancer immunotherapy; cyclic GMP-AMP synthase-stimulator of interferon genes pathway; metalloimmunotherapy; nanoagonists; photodynamic therapy

摘要："Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as an efficient strategy to improve the therapeutic outcomes of immunotherapy. However, the ""constantly active"" mode of current STING agonist delivery strategies typically leads to off-target toxicity and hyperimmunity. To address this critical issue, herein a metal-organic frameworks-based nanoagonist (DZ@A7) featuring tumor-specific and near-infrared (NIR) light-enhanced decomposition is constructed for precisely localized STING activation and photodynamic-metalloimmunotherapy. The engineered nanoagonist enabled the generation of mitochondria-targeted reactive oxygen species under NIR irradiation to specifically release mitochondrial DNA (mtDNA) and inhibit the repair of nuclear DNA via hypoxia-responsive drugs. Oxidized tumor mtDNA serves as an endogenous danger-associated molecular pattern that activates the cGAS-STING pathway. Concurrently, NIR-accelerated zinc ions overloading in cancer cells further enhance the cGAS enzymatic activity through metalloimmune effects. By combining the synergistically enhanced activation of the cGAS-STING pathway triggered by NIR irradiation, the engineered nanoagonist facilitated the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes for primary tumor eradication, which also established a long-term anti-tumor immunity to suppress tumor metastasis. Therefore, the developed nanoagonist enabled NIR-triggered, agonist-free, and tandem-amplified activation of the cGAS-STING pathway, thereby offering a distinct paradigm for photodynamic-metalloimmunotherapy. A decomposable nanoagonist is developed for agonists-free cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation. This process results in released mitochondrial DNA, inhibited nuclear DNA repair, and metal ions-boosted cGAS enzyme activity, synergistically facilitating the cGAS-STING activation. Combining these effects and the photodynamic-enhanced antitumor immune response, the nanoagonist enables an amplified photodynamic-metalloimmunotherapy of tumors. image"

基金机构："National Key Research and Development Projects; National Natural Science Foundation of China [(2021) 039]; China Postdoctoral Science Foundation (Pre-Station) [82171946, 52102350, 81873901]; Shanghai Science and Technology Program [2022TQ0396]; Basic Research Program of Shanghai Municipal Government [21010500100]; Shanghai Shuguang Program [21JC1406002]; Chenguang Program of Shanghai Education Development Foundation [21SG39]; Shanghai Municipal Education Commission; CQMU Program for Youth Innovation in Future Medicine; Basic Research and Frontier Exploration Key Project of Chongqing Science and Technology Commission [W0026]; Chongqing Science and Health Joint Medical Research Project-Young and Middle-aged High-level Talent Project [cstc2019jcyj-zdxmX0020]; [2023YFC2306500]; [2020GDRC011]"

基金资助正文："X.G., P.T., X.W., and C.D. contributed equally to this work. All animal experiments were approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University: Kelun prequalification no. (2021) 039. The authors greatly acknowledge the financial support from National Key Research and Development Projects (grant no. 2023YFC2306500), the National Natural Science Foundation of China (grant nos. 82171946, 52102350, 81873901), the China Postdoctoral Science Foundation (Pre-Station) (grant no. 2022TQ0396), the Shanghai Science and Technology Program (grant no. 21010500100), the Basic Research Program of Shanghai Municipal Government (grant no. 21JC1406002), Shanghai Shuguang Program (grant no. 21SG39), the Chenguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission, the CQMU Program for Youth Innovation in Future Medicine (grant no. W0026), the Basic Research and Frontier Exploration Key Project of Chongqing Science and Technology Commission (grant no. cstc2019jcyj-zdxmX0020), and the Chongqing Science and Health Joint Medical Research Project-Young and Middle-aged High-level Talent Project (grant no. 2020GDRC011)."