A metabolizable benzothiazole-based covalent organic framework nanodot enables photothermal-boosted cuproptosis for synergistic cancer therapy
Copper-based synergistic therapy integrating chemodynamic therapy (CDT) and cuproptosis holds promise for tumor treatment but faces clinical translation hurdles including long-term toxicity, low catalytic efficiency, off-target effects, and copper ion efflux. Here, we developed metabolizable ultrasmall benzothiazole-based covalent organic framework nanodots (COF NDs) via click condensation followed by liquid exfoliation. The dense donor-acceptor configurations confer a high photothermal conversion efficiency of 51.16%, while bisthiazole motifs enable specific Cu2+/Cu+ chelation (0.56:0.44), facile PEGylation, and mitochondrial targeting. These features enhance physiological stability and enable tumor-specific photothermal-catalytic synergy. Mitochondrial accumulation elevates intracellular copper to a critical threshold, inducing cuproptosis and suppressing tumor growth and metastasis. The NDs are efficiently excreted via renal and fecal pathways, demonstrating favorable biocompatibility and clinical potential as copper-based nanotherapeutics.