Authors
Minhao Jiang, Fang Pu, Yinuo Shu, Guoshi Xu, Jiawei Zhu, Yinghua Peng, Yanjie Zhang, Anjun Song, Jinsong Ren, Xiaogang Qu
Published in
Angewandte Chemie (International ed. in English). Pages e6633730. Jul 09, 2026. Epub Jul 09, 2026.
Abstract
Bioorthogonal chemistry, particularly the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, holds great promise for in situ prodrug activation to minimize systemic toxicity in disease treatments. However, existing approaches mainly rely on exogenous copper catalysts, which pose a risk of disrupting copper homeostasis and suffer from catalyst deactivation caused by cellular components. Moreover, the staggered administration of catalysts and prodrugs complicates clinical translation and leads to unpredictable reaction time windows. Herein, we construct a "one-stitch" bioorthogonal catalytic therapy system that harnesses endogenous copper without the need for copper supplements or external reductants. By integrating the DNAzyme CLICK-17 and the tumor-targeting aptamer AS1411 onto covalent organic framework (COF) nanoparticles, co-delivery of both the catalyst and the prodrugs in a single nanoplatform (COF-P@C-A) is achieved. Upon internalization by tumor cells, high intracellular glutathione (GSH) and an acidic environment triggered the degradation of COF nanoparticles to simultaneously release CLICK-17 and the prodrugs while consuming excess GSH, thereby alleviating copper sequestration and enhancing the availability of endogenous Cu(I). CLICK-17 then efficiently catalyzes the CuAAC reaction for localized drug synthesis, maximizing therapeutic efficacy and minimizing off-target effects. This strategy offers a safe, synchronized, and clinically translatable approach to bioorthogonal prodrug activation.
PMID:
42424162
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.
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