Cyclic Dinucleotide Self-Assembled Nanoparticles as a Carrier-Free Delivery Platform for STING-Mediated Cancer Immunotherapy  

作　　者：Lang Zhao Shao-Hua Zhuo Tian-Yang Wang Jun-Jun Wu Jing-Yun Su Wen-Hao Li Bo-Dou Zhang Yan-Mei Li 

机构地区：[1]Key Lab of Bioorganic Phosphorus Chemistry&Chemical Biology,Department of Chemistry,Tsinghua University,Beijing 100084 [2]Beijing Institute for Brain Disorders,Beijing 100069 [3]Center for Synthetic and Systems Biology,Tsinghua University,Beijing 100084

出　　处：《CCS Chemistry》2024年第1期177-195,共19页中国化学会会刊（英文）

基　　金：the National Key R&D Program of China(grant nos.2019YFA0904200 and 2018YFA0507600);the National Natural Science Foundation of China(grant nos.22237003 and 92053108);the Tsinghua University Spring Breeze Fund(grant no.2020Z99CFY042).

摘　　要：Cyclic dinucleotides(CDNs)are natural agonists of the stimulator of interferon genes(STING),which is an attractive immunotherapy target.Currently,CDNs and their derivatives are being investigated clinically.However,the poor bioavailability of exogenous CDNs has limited their application in immunotherapy.Although nanocarriers are widely used for cytosolic delivery of CDNs,their loading capacity is insufficient,and their complicated composition and purification process raises bio-compatibility concerns.Herein,we report a super-simplified CDN self-assembly strategy for carrier-free delivery of CDNs.In the presence of excess K^(+),CDNs form oligomers which further self-assemble with divalent metal ions(such as Mn^(2+))to form nanoparticles(NPs)in aqueous solution.We demonstrate that the self-assembled CDN NPs promote cellular uptake of CDNs and enhance tumor immunogenicity by remodeling the tumor microenvironment,inducing immunogenic tumor cell death and increasing tumorinfiltrating lymphocytes,which is conducive to the generation of tumor neoantigen-specific T-cell responses.We also demonstrate that the use of CDN NPs alone or in combination with immune checkpoint blockades inhibits tumor growth,highlighting the fact that CDN NPs are a potent platform for cancer immunotherapy.

关 键 词：cyclic dinucleotide STING carrierfree delivery tumor immunogenicity cancer immunotherapy 

分 类 号：R73[医药卫生—肿瘤]