CASTING: A Potent Supramolecular Strategy to Cytosolically Deliver STING Agonist for Cancer Immunotherapy and SARS-CoV-2 Vaccination  

作　　者：Jun-Jun Wu Fang-Yuan Chen Bei-Bei Han Hong-Qing Zhang Lang Zhao Zhe-Rui Zhang Juan-Juan Li Bo-Dou Zhang Ya-Nan Zhang Yu-Xin Yue Hong-Guo Hu Wen-Hao Li Bo Zhang Yong-Xiang Chen Dong-Sheng Guo Yan-Mei Li 

机构地区：[1]Key Lab of Bioorganic Phosphorus Chemistry and Chemical Biology(Ministry of Education),Department of Chemistry,Center for Synthetic and Systems Biology,Tsinghua University,Beijing 100084 [2]College of Chemistry,Key Laboratory of Functional Polymer Materials,Ministry of Education,State Key Laboratory of Elemento-Organic Chemistry,Nankai University,Tianjin 300071 [3]Key Laboratory of Special Pathogens and Biosafety,Center for Emerging Infectious Diseases,Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430071 [4]University of Chinese Academy of Sciences,Beijing 100049 [5]Beijing Institute for Brain Disorders,Beijing 100069 [6]Key Laboratory of Innate Immune Biology of Fujian Province,Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation,Biomedical Research Center of South China,College of Life Sciences,Fujian Normal University,Fuzhou 350117

出　　处：《CCS Chemistry》2023年第4期885-901,共17页中国化学会会刊（英文）

基　　金：supported by the National Key R&D Program of China(nos.2019YFA0904200 and 2018YFA0507600);the Tsinghua University Spring Breeze Fund(no.2020Z99CFY042);the National Natural Science Foundation of China(nos.92053108 and 31961143004);NCC Fund(no.NCC2020FH04).

摘　　要：Stimulator of interferon genes,namely STING,an adaptor protein located in the endoplasmic reticulum,has been recognized as a shining target for cancer and infection research.However,STING agonists cyclic dinucleotides(CDNs)have shown almost zero efficacy in phase I clinical trials as a monotherapy,likely due to poor cellular permeability and rapid diffusion despite intratumoral injection.These deficiencies further affect other applications of CDNs,such as pandemic SARS-CoV-2 prevention and therapy.Here,we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene,namely CASTING(CAlixarene-STING),to improve CDN druggability,including degradation stability,cellular permeability,and tissue retention.CASTING efficiently enhances the immunostimulatory potency of CDGSF[a chemically modified cyclic di-GMP(CDG)]to generate an immunogenic microenvironment for melanoma regression,anti-PD-1 response rate increase,and durable memory formation against tumor recurrence.More importantly,CASTING displays a superior adjuvant activity on SARSCoV-2 recombinant spike/receptor binding domain vaccines,inducing robust and coordinated T-cell and antibody responses against SARS-CoV-2 infection in vivo.Collectively,the CASTING design represents an innovative advancement to facilitate the clinical translational capability of STING agonists.

关 键 词：STING agonist cyclic dinucleotides CALIXARENE supramolecular delivery cancer immunotherapy SARS-CoV-2 vaccine adjuvant 

分 类 号：R730.51[医药卫生—肿瘤]