Tumor Microenvironment-Responsive and Catalytic Cascade-Enhanced Nanocomposite for Tumor Thermal Ablation Synergizing with Chemodynamic and Chemotherapy

Chemodynamic therapy (CDT) is considered as a promising nanocatalytic therapeutic strategy for cancer because of its specific response toward the tumor microenvironment (TME). Improving the efficiency of this kind of reactive oxygen species (ROS)-mediated therapy is still a formidable challenge. Herein, we integrate CDT with other therapeutic methods together to enhance anticancer effects via overcoming robust ROS defensive mechanisms and hypoxia in cancer cells. The biocompatible and biodegraded nanoplatform (HMnO2-DOX-GOD-HA) has been constructed on the basis of hollow MnO2 nanoparticles loaded with chemotherapeutics doxorubicin (DOX) and glucose oxide (GOD) and further decorated with hyaluronic acid (HA) for targeting tumor cells. We demonstrated that HMnO2-DOX-GOD-HA is not only able to deplete glutathione (GSH) to disturb the redox balance but also release Mn2+ to initiate the magnetic resonance imaging signal and induce Fenton reaction happening. Meanwhile, GOD-induced glucose oxidation and HMnO2-catalyzed O2 generation facilitate hypoxia relief and enhance toxic hydroxyl radical (•OH) production for CDT efficiency promotion. Upon 808 nm laser irradiation, cancer-killing efficiency can be notably increased by photothermally enhanced ion and drug release and thermal ablation. This work offers a paradigm to design a TME-responsive and imaging-guided synergistic strategy for hypoxia tumors based on GSH depletion and catalytic cascade-enhanced CDT, thermal ablation, and chemotherapy.