A nuclease-mimetic platinum nanozyme induces concurrent DNA platination and oxidative cleavage to overcome cancer drug resistance

Fangyuan Li, Heng Sun, Jiafeng Ren, Bo Zhang, Xi Hu, Chunyan Fang, Jiyoung Lee, Hongzhou Gu and Daishun Ling ()
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Fangyuan Li: Zhejiang University
Heng Sun: Zhejiang University
Jiafeng Ren: Zhejiang University
Bo Zhang: National Center for Translational Medicine, Shanghai Jiao Tong University
Xi Hu: Zhejiang University
Chunyan Fang: Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province
Jiyoung Lee: Zhejiang University
Hongzhou Gu: Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province
Daishun Ling: Zhejiang University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Platinum (Pt) resistance in cancer almost inevitably occurs during clinical Pt-based chemotherapy. The spontaneous nucleotide-excision repair of cancer cells is a representative process that leads to Pt resistance, which involves the local DNA bending to facilitate the recruitment of nucleotide-excision repair proteins and subsequent elimination of Pt-DNA adducts. By exploiting the structural vulnerability of this process, we herein report a nuclease-mimetic Pt nanozyme that can target cancer cell nuclei and induce concurrent DNA platination and oxidative cleavage to overcome Pt drug resistance. We show that the Pt nanozyme, unlike cisplatin and conventional Pt nanoparticles, specifically induces the nanozyme-catalyzed cleavage of the formed Pt-DNA adducts by generating in situ reactive oxygen species, which impairs the damage recognition factors-induced DNA bending prerequisite for nucleotide-excision repair. The recruitment of downstream effectors of nucleotide-excision repair to DNA lesion sites, including xeroderma pigmentosum groups A and F, is disrupted by the Pt nanozyme in cisplatin-resistant cancer cells, allowing excessive accumulation of the Pt-DNA adducts for highly efficient cancer therapy. Our study highlights the potential benefits of applying enzymatic activities to the use of the Pt nanomedicines, providing a paradigm shift in DNA damaging chemotherapy.

Date: 2022
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DOI: 10.1038/s41467-022-35022-w

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