Issue 19, 2024

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
18 feb 2024
Accepted
12 apr 2024
First published
16 apr 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 7079-7091

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

X. Wang, X. Ge, M. Zhang, J. Sun, J. Ouyang and N. Na, Chem. Sci., 2024, 15, 7079 DOI: 10.1039/D4SC01147C

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