Pyroptosis has attracted widespread concerns in cancer therapy, while the therapeutic efficiency could be significantly restricted by the crucial pyroptosis checkpoint of autophagy and tumor hypoxia. Herein, a DNA nanocomplex (DNFs@ZnMn), containing cascade DNAzymes, promoter-like ZnO2-Mn nanozymes and photosensitizers, was constructed in one pot through rolling circle amplification reactions to induce pyroptosis through disrupt autophagy. After targeted into cancer cells with high expression of H+ and glutathione, DNFs@ZnMn decomposed to expose DNAzymes and promoter-like ZnO2-Mn nanozyme. Then, sufficient metal ions and O2 were released to promote cascade DNA/RNA cleavage and relieving of tumor hypoxia. The released DNAzyme-1 self-cleaved long DNA strands with Zn2+ as cofactor and simultaneously exposed DNAzyme-2 to cleave ATG-5 mRNA (with Mn2+ as cofactor). This cascade DNAzyme-mediated gene regulation process induced downregulation of ATG-5 proteins to disrupt autophagy. Simultaneously, the released ZnO2 donated sufficient H2O2 to generate adequate O2 to relieve tumor hypoxia, obtaining high cytotoxic 1O2 to trigger pyroptosis. By dynamic cascade gene silencing to disrupt pyroptosis checkpoint and synergistical relieving of hypoxia, this DNA nanocomplex significantly weakened cellular resistance to achieve efficient pyroptosis therapy both in vitro and in vivo.

This article is Open Access

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