Tumor Microenvironment-Responsive Integrated Nanosystems for Enhanced Cuproptosis/Ferroptosis Anticancer Therapy

Copper-based nanomaterials hold immense potential for cancer therapy by inducing chemodynamic therapy and cuproptosis. However, their therapeutic efficacy is severely restricted by insufficient tumor accumulation, the potent antioxidant effects of elevated intracellular glutathione (GSH), and tumor adaptability to single-mechanism treatments. To address these challenges, we designed a pH/GSH dual-responsive nanosystem (CuSiO3@POM) by integrating molybdenum-based polyoxometalate (POM) clusters with a copper phyllosilicate platform. In the acidic tumor microenvironment (TME), POM drives in situ self-assembly into large aggregates, significantly enhancing tumor retention and local copper concentration. Upon cellular internalization, the elevated copper accumulation triggers cuproptosis; meanwhile, the overexpressed endogenous GSH reduces Cu2+ and Mo6+ to Cu+ and Mo5+, resulting in profound GSH depletion. Following this reduction, Cu+ catalyzes Fenton-like reactions to yield hydroxyl radicals (·OH), while Mo5+ generates singlet oxygen (1O2) via the Russell mechanism. This synergistic burst of reactive oxygen species triggers severe lipid peroxidation and subsequent ferroptosis. Furthermore, the reduced Mo5+ serves as an efficient agent for photothermal therapy (PTT) under NIR irradiation, which thermally amplifies the oxidative damage. By orchestrating cuproptosis, ferroptosis, and photothermal enhancement within a single TME-responsive platform, CuSiO3@POM provides a highly efficient multimodal strategy to overcome the limitations of conventional copper-based therapies.