Inhalable nanoparticles with enhanced cuproptosis and cGAS-STING activation for synergistic lung metastasis immunotherapy  

作　　者：Chongzheng Yan Huaiyou Lv Yafei Feng Yuhan Li Zhongxi Zhao 

机构地区：[1]Department of Pharmaceutics,Key Laboratory of Chemical Biology of Ministry of Education,School of Pharmaceutical Sciences,Cheelloo College of Medicine,Shandong University,Jinan 250012,China [2]Key University Laboratory of Pharmaceutics&Drug Delivery Systems of Shandong Province,School of Pharmaceutical Sciences,Cheeloo College of Medicine,Shandong University,Jinan 250012,China [3]Department of Pharmacy,Yantai Yuhuangding Hospital Affiliated to Qingdao University,Yantai 264001,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第8期3697-3710,共14页药学学报（英文版）

基　　金：funded by the Key R&D Programs of Shandong Province,China(Grant Nos.2018CXGC1411 and 2021CXGC010514).

摘　　要：Due to the insufficient Cu^(+)accumulation,Cu^(+)efflux mechanism,and highly immunosuppressive tumor microenvironment(TME)in lung metastasis,the cuproptosis efficacy is limited.Herein,an inhalable nanodevice(CLDCu)is constructed to successfully overcome the drawbacks of cuproptosis.CLDCu consists of a Cu^(2+)-chitosan shell and low molecular weight heparin-tocopherol succinate(LMWH-TOS,LT)core with disulfiram(DSF)loading.The prepared CLDCu can be inhaled and accumulate in large amounts in lung lesions(63.6%)with 56.5 times higher than intravenous injection.Within tumor cells,the mild acidity triggers the co-release of DSF and Cu2+,thus generating bis(diethyldithiocarbamate)-copper(CuET)to block Cu^(+)efflux protein ATP7B and forming toxic Cu^(+),leading to enhanced cuproptosis.Meanwhile,the released chitosan cooperates with CLDCu-induced cuproptosis to activate stimulator of interferon genes(STING)pathway,which significantly potentiates dendritic cells(DCs)maturation,as wells as evokes innate and adaptive immunity.In lung metastatic mice model,CLDCu is found to induce cuproptosis and reverse the immunosuppressive TME by inhalation administration.Moreover,CLDCu combined with anti-programmed cell death protein ligand-1 antibody(aPD-L1)provokes stronger antitumor immunity.Therefore,nanomedicine that combines cuproptosis with STING activation is a novel strategy for tumor immunotherapy.

关 键 词：Cuproptosis cGAS-STING activation DISULFIRAM Inhalation administration Tumor microenvironment PD-L1 checkpoint blockade Lung metastasis IMMUNOTHERAPY 

分 类 号：R730.51[医药卫生—肿瘤]