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.

在基于 Pt 的临床化疗过程中，几乎不可避免地会发生癌症中的铂 (Pt) 耐药性。癌细胞的自发核苷酸切除修复是导致 Pt 抗性的一个代表性过程，它涉及局部 DNA 弯曲以促进核苷酸切除修复蛋白的募集和随后消除 Pt-DNA 加合物。通过利用这一过程的结构脆弱性，我们在此报告了一种核酸酶模拟 Pt 纳米酶，它可以靶向癌细胞核并诱导同时发生的 DNA 铂化和氧化裂解以克服 Pt 耐药性。我们表明，与顺铂和常规 Pt 纳米颗粒不同，Pt 纳米酶通过原位产生活性氧物种特异性诱导形成的 Pt-DNA 加合物的纳米酶催化裂解，这削弱了核苷酸切除修复的损伤识别因子诱导的 DNA 弯曲先决条件。DNA 损伤位点（包括着色性干皮病 A 组和 F 组）的核苷酸切除修复下游效应子的募集被顺铂耐药癌细胞中的 Pt 纳米酶破坏，允许 Pt-DNA 加合物的过度积累以实现高效的癌症治疗. 我们的研究强调了将酶活性应用于 Pt 纳米药物的潜在好处，为 DNA 损伤化学疗法提供了范式转变。允许 Pt-DNA 加合物的过度积累以实现高效的癌症治疗。我们的研究强调了将酶活性应用于 Pt 纳米药物的潜在好处，为 DNA 损伤化学疗法提供了范式转变。允许 Pt-DNA 加合物的过度积累以实现高效的癌症治疗。我们的研究强调了将酶活性应用于 Pt 纳米药物的潜在好处，为 DNA 损伤化学疗法提供了范式转变。