Chitosan-coated, H₂O₂/pH dual-responsive manganese–magnesium oxide nanozyme for enhanced 5-fluorouracil delivery and synergistic colon cancer therapy

Colorectal cancer (CRC) treatment is often limited by low drug selectivity, systemic toxicity, and hypoxia within the tumor microenvironment (TME), reducing the efficacy of conventional chemotherapy. To address these challenges, we developed a dual-stimuli-responsive chitosan- manganese–magnesium oxide ( Mn–MgO@Chitosan ) nanozyme for controlled delivery of 5-fluorouracil (5-FLU) and catalytic modulation of the TME. The chitosan coating, a biocompatible carbohydrate polymer, provided a high surface area (104.78 m ² /g) for efficient drug loading while stabilizing the spherical nanostructure. Drug release was accelerated under acidic and hydrogen peroxide (H₂O₂)-rich conditions, and the Mn–MgO core exhibited peroxidase- and catalase-like activities, generating hydroxyl radicals (•OH) for chemodynamic therapy (CDT) and producing oxygen (O₂) to alleviate hypoxia. In vitro studies using HCT-116 CRC cells demonstrated that Mn–MgO@Chitosan@5-FLU achieved 87.83% cumulative drug release and induced 77.04% growth inhibition, outperforming free 5-FLU or the unloaded nanozyme. Enhanced cytotoxicity was associated with elevated intracellular reactive oxygen species (ROS) and activation of both intrinsic and extrinsic apoptotic pathways, while the system maintained excellent biocompatibility with normal cells. Overall, this carbohydrate-polymer-enabled nanozyme effectively combines chemotherapy and catalytic therapy, offering a precise and potent approach for CRC treatment.