Cascade enzymatic semiconducting polymer nanocomposites for NIR-II light-mediated photothermal-chemodynamic combinatorial therapy

Chemodynamic therapy (CDT) has been widely adopted for cancer therapy, but its efficacy is limited by some factors such as low intratumoral H₂O₂ level and glutathione (GSH) scavenging in the tumor microenvironment (TME). NIR-II photothermal therapy (PTT) enhances catalytic kinetics and alleviates TME restrictions <i>via</i> deep tissue penetration and spatiotemporally controlled hyperthermia. Herein, we report a tumor-targeted nanocomposite called SPMG by integrating bovine serum albumin (BSA)-MnO₂, a semiconducting polymer (SP_II), and glucose oxidase (GOx) to enable NIR-II-triggered PTT and enzyme-augmented CDT. The semiconducting polymer SP_II shows high NIR-II photothermal conversion efficiency (<i>λ</i> = 1064 nm) to enable precision PTT through tumor-localized hyperthermia. It drives self-assembly with BSA-MnO₂<i>via</i> nano-coprecipitation to form SPM, which serves as stable carrier for GOx immobilization. The resultant nanocomposites (SPMG) synergize the dual therapeutic modalities in addition to NIR-II PTT: MnO₂ releases Mn²⁺ ions for CDT <i>via</i> Mn²⁺-catalyzed Fenton-like reaction and GOx-mediated glucose oxidation to generate endogenous H₂O₂. This cascade fuels Mn²⁺-catalyzed reaction, thus achieving self-enhanced CDT through ˙OH burst, with concurrent mild hyperthermia (≤45 °C) for amplifying enzymatic activity and tumor-specific ROS accumulation. This NIR-II light-mediated PTT-CDT combinatorial therapy enables effective treatments of subcutaneous 4T1 tumors in mouse models.