Tumor-responsive covalent organic polymeric nanoparticles enhancing STING activation for cancer immunotherapy  

作　　者：Shuang Liang Jianjun Yao Dan Liu Mengli Zhou Yong Cui Zhaohui Wang 

机构地区：[1]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China [2]School of Life Sciences and Biopharmaceutical Science,Shenyang Pharmaceutical University,Shenyang 110016,China [3]Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China

出　　处：《Chinese Chemical Letters》2025年第3期357-362,共6页中国化学快报(英文版)

基　　金：supported by the Beijing Natural Science Foundation(No.Z230021);the National Natural Science Foundation of China(No.52202356);the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2021-RC350-001);the CAMS Innovation Fund for Medical Sciences(No.2022-I2M-1-013).

摘　　要：The cyclic guanosine monophosphate-adenosine monophosphate synthase and the stimulator of interferon genes(cGAS-STING)has emerged as a promising target for cancer immunotherapy.However,the development of natural STING agonists is impeded by several challenges,including limited biostability,poor pharmacokinetics,and inefficient cytosolic delivery.Herein,we meticulously designed a doublelayer polyethylenimine(PEI)modified nanoscale covalent organic polymer(CPGP)for efficient delivery of 23cyclic guanosine monophosphate-adenosine monophosphate(cGAMP),a natural STING agonist.The double-layer PEI structured CPGP enhanced both the loading capacity and stability of cGAMP.Furthermore,CPGP improved the intracellular delivery efficiency and amplified the activation of STING pathway for the secretion of type-I interferon and pro-inflammatory cytokines.In contrast,single-layered nanoparticles failed to permit stable loading and intracellular delivery of cGAMP for immune response.The nano-STING agonist also mitigated the immunosuppressive tumor microenvironment(TME)by reducing regulatory T cells and polarizing M2 macrophages to the M1 phenotype,thereby creating an immune-supportive TME to enhance adaptive immune responses.The combination of CPGP and immune checkpoint blockers showed synergistic effect,further enhancing the inhibition effect on tumor growth.This double-layer PEI modified CPGP may offer a generalizable platform for other natural dinucleotide STING agonists to overcome the cascade delivery barriers,augmenting immune activation for tumor immunotherapy.

关 键 词：IMMUNOTHERAPY Covalent organic polymers Delivery STING agonists NANOPARTICLE 

分 类 号：R730.51[医药卫生—肿瘤]