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 HO level and glutathione (GSH) scavenging in the tumor microenvironment (TME). NIR-II photothermal therapy (PTT) enhances catalytic kinetics and alleviates TME restrictions deep tissue penetration and spatiotemporally controlled hyperthermia. Herein, we report a tumor-targeted nanocomposite called SPMG by integrating bovine serum albumin (BSA)-MnO, a semiconducting polymer (SP), and glucose oxidase (GOx) to enable NIR-II-triggered PTT and enzyme-augmented CDT. The semiconducting polymer SP shows high NIR-II photothermal conversion efficiency ( = 1064 nm) to enable precision PTT through tumor-localized hyperthermia. It drives self-assembly with BSA-MnO 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: MnO releases Mn ions for CDT Mn-catalyzed Fenton-like reaction and GOx-mediated glucose oxidation to generate endogenous HO. This cascade fuels Mn-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.