NIR-II responsive copper-nitrogen doped photocatalysts for pyroptosis and cuproptosis

Based on their distinctive manners of driving cell death, cuproptosis and pyroptosis exhibit significant potential in overcoming the apoptosis resistance of cancer cells. Nevertheless, limited copper concentrations and complex tumor microenvironment (TME) severely constrain the therapeutic efficacy. Herein, DSPE-PEG₂₀₀₀ modified copper-nitrogen-doped carbon-based photocatalysts (Cu-NC@PEG) are developed as photo-activated reactive oxygen species (ROS) amplification systems to trigger pyroptosis and cuproptosis in a synergistic manner. Cu-NC@PEG enriches in tumor cells and generates a large amount of superoxide anions under the second near-infrared region (NIR-II) laser irradiation, followed by further induction of cell pyroptosis through caspase-mediated cleavage of Gasdermin D (GSDMD). The copper ions released from Cu-NC@PEG in the acidic TME can not only generate ·OH and consume the antioxidants to enhance ROS-induced pyroptosis, but also effectively activate cuproptosis through Cu⁺-mediated dihydrolipoamide S-acetyltransferase aggregation and Fe-S cluster protein loss. Simultaneously, the mitochondrial damage induced by pyroptosis leads to a considerable efflux of ATP and the restricted ATP availability could enhance the disruption of copper metabolic homeostasis, thereby potentiating cuproptosis. The increased tumor-inhibiting effects of the combined induction of cuproptosis and pyroptosis could be achieved. STATEMENT OF SIGNIFICANCE: 1. NIR-II photo-activated copper-nitrogen-doped carbon-based photocatalysts (Cu-NC@PEG) were developed. 2. ROS amplification was achieved based on the photo catalytic properties and Fenton-like reaction of Cu-NC@PEG. 3. Therapeutic efficacy was enhanced via ROS-induced pyroptosis and Cu⁺-mediated cuproptosis.