NIR-II-/Tumor Acidity-Triggered Nanoplatform for Precise Chemodynamic/Photodynamic/Hypoxia-Activated Chemo Trimodal Synergistic Therapy

Engineering stimuli-responsive nanoplatforms for multimodal therapeutics to combat the diversity, complexity, and heterogeneity of malignant tumors has emerged as a new research focus. Herein, chitosan (CS)-based nanoplatforms coloaded with copper selenide quantum dots (Cu2–xSe QDs) and tirapazamine (TPZ) were prepared by a facile ion-cross-linking method (CS/Cu2–xSe-TPZ NPs) to achieve stimuli-responsive precise chemodynamic-/photodynamic-/chemotherapy-based trimodal tumor therapy. Triggered by the endogenous tumor acidic microenvironment and the exogenous second near-infrared (NIR-II) light, Cu2–xSe QDs efficiently generated dreadful radicals (•OH and 1O2) to achieve efficient Cu2–xSe-based synergistic chemodynamic therapy (CDT) and photodynamic therapy (PDT). Subsequently, PDT-induced hypoxia activated the cytotoxic potential of TPZ, thus inciting a hypoxia-specific chemotherapeutic effect. The synergistic tumor suppression effect of the trimodal therapy could overcome the hindrance of the tumor microenvironment, showing remarkable therapeutic effects in vitro and in vivo. Together, this work unveiled the potential of engineered stimuli-responsive nanoplatforms by integrating NIR-II-induced PDT, acidity-boosted CDT, and hypoxia-activated chemotherapy, offering potential solutions to current challenges in cancer therapy.