A dynamic cascade DNA nanocomplex to synergistically disrupt the pyroptosis checkpoint and relieve tumor hypoxia for efficient pyroptosis cancer therapy

Abstract

Pyroptosis has attracted widespread concerns in cancer therapy, while the therapeutic efficiency could be significantly restricted by using 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 disrupting autophagy. After targeting cancer cells with a high expression of H⁺ and glutathione, DNFs@ZnMn decomposed to expose DNAzymes and promoter-like ZnO₂–Mn nanozymes. 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 the cofactor and simultaneously exposed DNAzyme-2 to cleave ATG-5 mRNA (with Mn²⁺ as the 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 highly cytotoxic ¹O₂ to trigger pyroptosis. By using dynamic cascade gene silencing to disrupt the pyroptosis checkpoint and synergistic relieving of hypoxia, this DNA nanocomplex significantly weakened cellular resistance to achieve efficient pyroptosis therapy both in vitro and in vivo.