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

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 (CuMnO_x-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 CuMnO_x-V nanozymes with excellent catalytic activity. In the tumor microenvironment (TME), CuMnO_x-V nanozymes exhibit peroxidase, oxidase, and NAD⁺ oxidase-mimicking activities. CuMnO_x-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.