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Co-delivery of nigericin and decitabine using hexahistidine-metal nanocarriers for pyroptosis-induced immunotherapeutics

查看全文 作　　者：Qiang [1]Niu;Yu [2]Liu;Yujing [2]Zheng;Ziwei [1]Tang;Yuna [2,3]Qian;Ruogu [4]Qi;Jianliang [2,3]Shen;Ping [1]Zhao 高影响力作者 机构地区：[1]School of Chemistry and Chemical Engineering,Guangdong Pharmaceutical University,Guangzhou 510006,China;[2]State Key Laboratory of Ophthalmology,Optometry and Vision Science,School of Ophthalmology and Optometry,School of Biomedical Engineering,Wenzhou Medical University,Wenzhou 325027,China;[3]Wenzhou Institute,University of Chinese Academy of Sciences,Wenzhou 325001,China;[4]School of Medicine&Holistic Integrative Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China高影响力机构 出　　处：《Acta Pharmaceutica Sinica B》索引2022年第12卷第12期,共14页高影响力期刊 基　　金：This work was financially supported by the National Nature Science Foundation of China(No.21671150,52073145,21877084);the Key Research Projects of Guangdong Province(NO.2021ZDZX4019). 摘　　要：Pyroptosis provides a new window for relieving the tumor immunosuppressive microenvironment(TIM)and promoting systemic immune responses for tumor treatments.However,gasdermin D(GSDMD),a key protein in the pyroptosis process mediated by caspase-1,is low expressed in the majority of tumor cells and small-molecule inhibitors of DNA methylation suffer from nonspecific or single-function defects.To address these issues,hexahistidine(His6)-metal assembly(HmA)was employed as the drug delivery vector to load nigericin(Nig)and decitabine(DAC)affording a dual-drug delivery system(Nig^(+)DAC)@HmA.The(Nig^(+)DAC)@HmA nanoparticles are efficiently internalized by cells through endocytosis,easily escape from the lysosome,and are highly distributed in the tumor sites.DAC up-regulates the expression of GSDMD which is then cleaved by the nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inflammasome and caspase-1 protein activated by Nig.Effective cancer cell pyroptosis is thus achieved and induces a significant systemic antitumor immunity for impressive tumor suppression with negligible side effects in vivo.Our results suggest that such an easy-to-manipulate self-assembled nano-system(Nig^(+)DAC)@HmA provides a new anticancer path by enhancing pyroptosis through reinforced inflammation. 关 键 词：Self-assembled nanoparticle PYROPTOSIS NLRP3 GSDMD Inflammation IL-8 Immunotherapy responses Solid tumor
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