Genetically engineered nanomodulators elicit potent immunity against cancer stem cells by checkpoint blockade and hypoxia relief  

作　　者：Yuanwei Pan Ling Yu Lujie Liu Jing Zhang Shuang Liang Badri Parshad Jialin Lai Li-Min Ma Zhaohui Wang Lang Rao 

机构地区：[1]The Research and Application Center of Precision Medicine,The Second Affiliated Hospital of Zhengzhou University,Zhengzhou,450014,China [2]Institute of Biomedical Health Technology and Engineering,Shenzhen Bay Laboratory,Shenzhen,518132,China [3]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 [4]Department of Critical Care Medicine,Guangdong Provincial Hospital of Chinese Medicine,Guangzhou,510120,China [5]Medical Research Center,Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences),Southern Medical University,Guangzhou,510080,China [6]Wellman Center for Photomedicine,Massachusetts General Hospital,Harvard Medical School,Boston,MA,02129,USA

出　　处：《Bioactive Materials》2024年第8期31-44,共14页生物活性材料（英文）

基　　金：supported by the National Natural Science Foundation of China(Nos.82222035 and 82372106);the Guangdong Basic and Applied Basic Research Foundation(No.2023A1515110633);the Shenzhen Medical Research Found(No.B2302041);the Shenzhen Science and Technology Program(No.RCBS20221008093123060);the Shenzhen Bay Laboratory Proof-of-Concept Fund(No.S231801005).

摘　　要：Rapid development of checkpoint inhibitors has provided significant breakthroughs for cancer stem cell(CSC)therapy,while the therapeutic efficacy is restricted by hypoxia-mediated tumor immune evasion,especially hypoxia-induced CD47 overexpression in CSCs.Herein,we developed a genetically engineered CSC membrane-coated hollow manganese dioxide(hMnO_(2)@gCMs)to elicit robust antitumor immunity by blocking CD47 and alleviating hypoxia to ultimately achieve the eradication of CSCs.The hMnO_(2)core effectively alleviated tumor hypoxia by inducing decomposition of tumor endogenous H_(2)O_(2),thus suppressing the CSCs and reducing the expression of CD47.Cooperating with hypoxia relief-induced downregulation of CD47,the overexpressed SIRPαon gCM shell efficiently blocked the CD47-SIRPα“don’t eat me”pathway,synergistically eliciting robust antitumor-mediated immune responses.In a B16F10-CSC bearing melanoma mouse model,the hMnO_(2)@gCMs showed an enhanced therapeutic effect in eradicating CSCs and inhibiting tumor growth.Our work presents a simple,safe,and robust platform for CSC eradication and cancer immunotherapy.

关 键 词：Cancer immunotherapy Cancer stem cells HYPOXIA CD47-SIRPα Cell membrane vesicles 

分 类 号：R730.3[医药卫生—肿瘤]