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

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 (hMnO2@gCMs) to elicit robust antitumor immunity by blocking CD47 and alleviating hypoxia to ultimately achieve the eradication of CSCs. The hMnO2 core effectively alleviated tumor hypoxia by inducing decomposition of tumor endogenous H2O2, thus suppressing the CSCs and reducing the expression of CD47. Cooperating with hypoxia relief-induced downregulation of CD47, the overexpressed SIRPα on 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 hMnO2@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. A novel genetically engineered biomimetic nanoplatform was developed to trigger the immunity against the CSCs through hypoxia relief and synergetic inhibition of the CD47-SIRPα signaling pathway. The work presented here provides a simple, safe, and effective strategy in activating body's immune responses for eradication of the CSCs. [Display omitted] •Hypoxia relief by hMnO2@gCMs could suppress CSCs and reduce CD47 expression.•hMnO2@gCMs block the CD47-SIRPα pathway via overexpressed SIRPα on gCMs shell.•Hypoxia relief-induced downregulation of CD47 and CD47-SIRPα blockade synergistically elicit robust antitumor immune responses.•hMnO2@gCMs present enhanced therapeutic efficacy in eradicating CSCs.