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

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 tumo...

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Bibliographic Details
Main Authors: Dong Zhong, Xiaoxin Yang, Jinhui Yang, Zhisheng Luo, Zhichao Feng, Mengtian Ma, Yunjie Liao, Yongxiang Tang, Yu Wen, Jun Liu, Shuo Hu
Format: Article
Language:English
Published: BMC 2025-05-01
Series:Journal of Nanobiotechnology
Subjects:
ETC disruption
Bimetallic nanozymes
NAD+ depletion
Multi-enzyme activity
Oxaliplatin resistance
Online Access:https://doi.org/10.1186/s12951-025-03417-8
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Summary: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.
ISSN:1477-3155

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