A metabolizable benzothiazole-based covalent organic framework nanodot enables photothermal-boosted cuproptosis for synergistic cancer therapy

Copper-based synergistic therapy integrating chemodynamic therapy and cuproptosis holds great promise for tumor treatment due to its streamlined processes and enhanced efficacy. However, its clinical translation is hampered by the potential long-term toxicity, low catalytic efficiency, off-target effects, and ion efflux of copper. Herein, we developed metabolizable ultrasmall benzothiazole-based covalent organic framework nanodots (COF NDs) through a click condensation reaction followed by liquid exfoliation. The dense donor-acceptor configurations endow the NDs with a high photothermal conversion efficiency (51.16%), while the bisthiazole motifs enable specific Cu 2+ /Cu + chelation (0.56:0.44), facile PEGylation, and mitochondrial targeting. These features collectively enhance physiological stability and enable tumor-specific photothermal-catalytic synergy. Importantly, mitochondrial accumulation of the NDs elevates intracellular copper to a critical threshold, thereby inducing cuproptosis and effectively suppressing tumor growth and metastasis. Furthermore, the NDs are efficiently excreted via renal and fecal pathways, demonstrating favorable bio-compatibility and highlighting their strong clinical potential as copper-based nanotherapeutics.