Key Takeaways & Executive Findings
- •• • 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.
Abstract
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.
1. Introduction
Conventional copper-based cancer therapies, including chemodynamic therapy (CDT) and cuproptosis, are constrained by two fundamental bottlenecks: cellular copper homeostasis actively exports ions via transporters such as ATP7A, preventing the intracellular accumulation necessary for cuproptosis, and the catalytic efficiency of transition-metal CDT is optimal under acidic conditions, whereas the tumor cytoplasm maintains near-neutral pH, severely limiting therapeutic efficacy. These limitations have hindered clinical translation despite the promise of synergistic approaches.
Nanotechnology has sought to address these issues through copper delivery vehicles and nanozymes, with recent advances in single-site nanozymes (SSNzymes) offering atomically dispersed active sites that maximize metal utilization and maintain activity across a broad pH range. However, existing SSNzyme platforms suffer from inadequate tumor selectivity, off-target toxicity, inefficient metal ion release, and unresolved long-term biosafety due to poor metabolic clearance. The present work introduces a metabolizable benzothiazole-based covalent organic framework nanodot (BCCP ND) that integrates photothermal properties with single-site copper chelation, enabling mitochondrial targeting and efficient renal/fecal excretion, thereby overcoming these critical bottlenecks.
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DONG Ganlin, ZOU Meizhen, LI Shuting, WANG Yahuan, LIU Yan, HU Liefeng (2026). A metabolizable benzothiazole-based covalent organic framework nanodot enables photothermal-boosted cuproptosis for synergistic cancer therapy. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-4026-0
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Frequently Asked Questions
What is the photothermal conversion efficiency (PCE) of the BCCP ND, and how does it compare to existing photothermal agents?
The BCCP ND exhibits a PCE of 51.16%, which is competitive with or superior to many inorganic and organic photothermal agents. This high efficiency enables effective photothermal heating at low laser power densities, reducing potential thermal damage to surrounding healthy tissues.
How does the BCCP ND achieve cuproptosis induction despite cellular copper efflux mechanisms?
The BCCP ND specifically targets mitochondria via its benzothiazole moieties, delivering copper ions directly to the organelle where cuproptosis occurs. Mitochondrial accumulation elevates local copper concentration beyond the threshold required to trigger lipoylated protein aggregation and Fe-S cluster destabilization, overwhelming efflux pumps such as ATP7A.
What is the catalytic mechanism of BCCP ND under neutral pH conditions, and how does it overcome the pH limitation of conventional CDT?
The single-site chelated Cu2+/+ in BCCP ND exhibits POD-like and GSHOx-like activities that generate reactive oxygen species (ROS) even at neutral pH. This is attributed to the electron-rich benzothiazole framework and the coordination environment, which lower the activation energy for Fenton-like reactions, unlike free copper ions that require acidic conditions.
What is the metabolic clearance profile of BCCP ND, and how does it address long-term toxicity concerns?
Due to its ultra-small size, BCCP ND is efficiently excreted via both renal (urine) and fecal pathways. In vivo studies showed that liver and kidney function biomarkers (ALT, AST, BUN, CRE) remained within normal ranges, indicating no obvious toxicity. This rapid clearance minimizes systemic accumulation and long-term adverse effects, a critical requirement for clinical translation.
How does photothermal therapy (PTT) synergize with cuproptosis in this system?
The photothermal effect (PCE 51.16%) elevates local temperature, which enhances the catalytic activity of BCCP ND, increasing ROS generation and accelerating copper-induced cuproptosis. This synergy amplifies antitumor efficacy, suppresses tumor growth and metastasis, and may reduce required therapeutic doses, potentially lowering side effects.
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