ROS-amplifying HKUST-1 nanozyme for enhanced colon cancer therapy

The development of effective strategies to amplify reactive oxygen species (ROS) within tumors has great potential to improve colon cancer therapy. In this study, we developed a multifunctional nanozyme platform (HHOC) based on the copper metal-organic framework HKUST-1, co-loading the photosensitizer chlorin e6 (Ce6) and the chemotherapeutic agent oxaliplatin (OXA), with surface modification by hyaluronic acid (HA). Benefiting from HA-mediated CD44 targeting, HHOC preferentially accumulated in colon cancer cells, resulting in enhanced cellular uptake. Upon laser irradiation, Ce6 generated abundant singlet oxygen to induce photodynamic therapy. Meanwhile, the HKUST-1 nanozyme exhibited peroxidase-like activity, with its Cu²⁺ sites readily reduced by the elevated intracellular glutathione to Cu⁺, which depleted this key antioxidant and impaired cellular redox homeostasis. The generated Cu⁺ further catalyzed endogenous hydrogen peroxide through Fenton-like reactions to produce highly cytotoxic hydroxyl radicals, thereby amplifying ROS-mediated oxidative stress. Moreover, HKUST-1 converted light energy into heat, producing a photothermal effect that promoted tumor cell damage and accelerated drug release. Released OXA exerted chemotherapeutic cytotoxicity, synergizing with ROS-mediated therapies. In vivo studies using CT26 tumor-bearing mice demonstrated that HHOC achieved a tumor growth inhibition rate of 94.51 %, confirming the efficacy of this ROS-amplifying nanozyme platform. This work presents HKUST-1-based nanozyme as an effective approach for multimodal colon cancer therapy through enhanced ROS generation and combinational treatment modalities.