• • Photothermal conversion efficiency (PCE) of 51.16% was achieved, enabling localized hyperthermia that boosts catalytic activity and cuproptosis efficacy, critical for synergistic therapy.
• • The COF NDs chelate Cu2+/Cu+ at a ratio of 0.56:0.44, providing single-site catalytic centers with POD-like and GSHOx-like activities that generate ROS even under neutral pH, overcoming a key limitation of conventional CDT.
• • In vivo studies confirmed efficient renal and fecal excretion, with liver and kidney function biomarkers (ALT, AST, BUN, CRE) remaining within normal ranges, indicating no obvious toxicity and addressing long-term biosafety concerns.
• • The NDs exhibit mitochondrial targeting, elevating intracellular copper to trigger cuproptosis, effectively suppressing tumor growth and metastasis, as demonstrated in vitro and in vivo.