Pyroptosis provides a new window for relieving the tumor immunosuppressive microenviron-ment(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 ma-jority 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 em-ployed 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 olig-omerization 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 immu-nity 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.

Qiang Niu;Yu Liu;Yujing Zheng;Ziwei Tang;Yuna Qian;Ruogu Qi;Jianliang Shen;Ping Zhao

School of Chemistry and Chemical Engineering,Guangdong Pharmaceutical University,Guangzhou 510006,China;State Key Laboratory of Ophthalmology,Optometry and Vision Science,School of Ophthalmology and Optometry,School of Biomedical Engineering,Wenzhou Medical University,Wenzhou 325027,China;Wenzhou Institute,University of Chinese Academy of Sciences,Wenzhou 325001,China;School of Medicine&Holistic Integrative Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China

药学学报（英文版）

[1]Qiang Niu;Yu Liu;Yujing Zheng;Ziwei Tang;Yuna Qian;Ruogu Qi;Jianliang Shen;Ping Zhao-.Co-delivery of nigericin and decitabine using hexahistidine-metal nanocarriers for pyroptosis-induced immunotherapeutics)[J].药学学报（英文版）,2022(12):4458-4471

hexahistidine,immunotherapeutics,HmA,Nig,Nig+DAC,olig,omerization

Co,delivery,nigericin,decitabine,using,metal,nanocarriers,pyroptosis,induced,Pyroptosis,provides,new,window,relieving,immunosuppressive,microenviron,TIM,promoting,systemic,immune,responses,treatments,However,gasdermin,GSDMD,key,protein,process,mediated,by,caspase,low,expressed,jority,cells,small,molecule,inhibitors,methylation,suffer,from,nonspecific,single,function,defects,To,address,these,issues,His6,assembly,was,ployed,drug,vector,load,affording,dual,nanoparticles,are,efficiently,internalized,through,endocytosis,easily,escape,lysosome,highly,distributed,sites,regulates,expression,which,then,cleaved,nucleotide,binding,domain,like,receptor,NLRP3,inflammasome,activated,Effective,thus,achieved,induces,significant,antitumor,nity,impressive,suppression,negligible,side,effects,vivo,Our,results,suggest,that,such,easy,manipulate,self,assembled,anticancer,path,enhancing,reinforced,inflammation

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