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