Boosting Reactive Oxygen Species Generation with a Dual-Catalytic Nanomedicine for Enhanced Tumor Nanocatalytic Therapy

Generating lethal reactive oxygen species (ROS) within tumors by nanocatalytic medicines is an advanced strategy for tumor-specific therapy in recent years. Nevertheless, the low yield of ROS restrains its therapeutic efficiency. Herein, a dual-catalytic nanomedicine based on tumor microenvironment (TME)-responsive liposomal nanosystem co-delivering CuO₂ and dihydroartemisinin (DHA) (LIPSe@CuO₂&DHA) is developed to boost ROS generation against tumor. The liposomal nanosystem can degrade in the ROS-overexpressed TME and liberate CuO₂ and DHA to initiate Cu-based dual-catalytic ROS generation. Serving as generators of H₂O₂ and Cu²⁺, CuO₂ can self-produce plenty of toxic hydroxyl radicals via Fenton-like reaction in the acidic TME. Meanwhile, the released Cu²⁺ can catalyze DHA to generate cytotoxic C-centered radicals. Together, the self-supplied H₂O₂ and Cu-based dual-catalytic reaction greatly increase the intratumoral level of lethal ROS. Importantly, Cu²⁺ can decrease the GSH-mediated scavenging effect on the produced ROS via a redox reaction and undergo a Cu²⁺-to-Cu⁺ conversion to enhance the Fenton-like reaction, further guaranteeing the high efficiency of ROS generation. Resultantly, LIPSe@CuO₂&DHA induces remarkable cancer cell death and tumor growth inhibition, which may present a promising nanocatalytic medicine for cancer therapy.