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<p>In colorectal cancer treatment, chemotherapeutic agents induce reactive oxygen species (ROS) production, which promotes NAD<sup>+</sup> accumulation in tumor cells, reducing treatment sensitivity and worsening patient prognosis. Targeted depletion of NAD<sup>+</sup> presents a promising strategy to overcome tumor resistance and improve patient prognosis. Here, we designed a dual-metallic nanozyme (CuMnO<sub>x−V</sub>@Oxa@SP) with defect engineering, modified by soy phospholipids (SP) and loaded with oxaliplatin (Oxa). This nanozyme uses its oxygen-deficient active sites to rapidly and irreversibly degrade NAD⁺ and NADH into nicotinamide and ADP-ribose derivatives, disrupting the electron transport chain (ETC) and compromising tumor antioxidant defenses. It also inhibits the glutathione S-transferase P1 (GSTP1) pathway, weakening tumor detoxification and enhancing chemotherapy sensitivity. Density functional theory calculations revealed that the synergistic effect among multi-enzyme active centers endows the CuMnO<sub>x−V</sub> nanozymes with excellent catalytic activity. In the tumor microenvironment (TME), CuMnO<sub>x−V</sub> nanozymes exhibit peroxidase, oxidase, and NAD<sup>+</sup> oxidase-mimicking activities. CuMnO<sub>x−V</sub> generates multiple ROS and depletes NAD<sup>+</sup> while preventing their regeneration thereby triggering a cascade amplification of oxidative stress. This, coupled with targeted chemotherapy drug delivery, restores chemosensitivity in refractory tumors and exposes the vulnerabilities of resistant colorectal cancer cells to ROS.</p>

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Oxygen vacancy-engineered bimetallic nanozymes for disrupting electron transport chain and synergistic multi-enzyme activity to reverse oxaliplatin resistance in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月16日

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  • Dong Zhong,
  • Xiaoxin Yang,
  • Jinhui Yang,
  • Zhisheng Luo,
  • Zhichao Feng,
  • Mengtian Ma,
  • Yunjie Liao,
  • Yongxiang Tang,
  • Yu Wen,
  • Jun Liu,
  • Shuo Hu

摘要

In colorectal cancer treatment, chemotherapeutic agents induce reactive oxygen species (ROS) production, which promotes NAD+ accumulation in tumor cells, reducing treatment sensitivity and worsening patient prognosis. Targeted depletion of NAD+ presents a promising strategy to overcome tumor resistance and improve patient prognosis. Here, we designed a dual-metallic nanozyme (CuMnOx−V@Oxa@SP) with defect engineering, modified by soy phospholipids (SP) and loaded with oxaliplatin (Oxa). This nanozyme uses its oxygen-deficient active sites to rapidly and irreversibly degrade NAD⁺ and NADH into nicotinamide and ADP-ribose derivatives, disrupting the electron transport chain (ETC) and compromising tumor antioxidant defenses. It also inhibits the glutathione S-transferase P1 (GSTP1) pathway, weakening tumor detoxification and enhancing chemotherapy sensitivity. Density functional theory calculations revealed that the synergistic effect among multi-enzyme active centers endows the CuMnOx−V nanozymes with excellent catalytic activity. In the tumor microenvironment (TME), CuMnOx−V nanozymes exhibit peroxidase, oxidase, and NAD+ oxidase-mimicking activities. CuMnOx−V generates multiple ROS and depletes NAD+ while preventing their regeneration thereby triggering a cascade amplification of oxidative stress. This, coupled with targeted chemotherapy drug delivery, restores chemosensitivity in refractory tumors and exposes the vulnerabilities of resistant colorectal cancer cells to ROS.