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

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

  • J Nanobiotechnology. 2025 May 16;23(1):352. doi: 10.1186/s12951-025-03417-8.
Dong Zhong 1,  Xiaoxin Yang 2,  Jinhui Yang 1,  Zhisheng Luo 1,  Zhichao Feng 3,  Mengtian Ma 4,  Yunjie Liao 5,  Yongxiang Tang 1,  Yu Wen 6,  Jun Liu 7,  Shuo Hu 8 9 10
Affiliations

Affiliations

  • 1 Department of Nuclear Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China.
  • 2 Department of Radiology, Second Xiangya Hospital of Central South University, 139 Renming Middle Road Changsha, Changsha, Hunan, China. yxxawy@163.com.
  • 3 SJTU-Ruijin-UIH Institute for Medical Imaging Technology Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Department of Radiology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China.
  • 5 Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 6 Furong Laboratory, Central South University, Changsha, Hunan, 410008, China.
  • 7 Department of Radiology, Second Xiangya Hospital of Central South University, 139 Renming Middle Road Changsha, Changsha, Hunan, China. junliu123@csu.edu.cn.
  • 8 Department of Nuclear Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China. hushuo2018@163.com.
  • 9 National Clinical Research Center for Geriatric Disorders (XIANGYA), Xiangya Hospital, Central South University, Changsha, Hunan, China. hushuo2018@163.com.
  • 10 Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital, Central South University, Changsha, Hunan, China. hushuo2018@163.com.
PMID: 40380190 DOI: 10.1186/s12951-025-03417-8
Abstract

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.

Keywords

Bimetallic nanozymes; ETC disruption; Multi-enzyme activity; NAD+ depletion; Oxaliplatin resistance.

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