Click‐Activated Supramolecular Targeting Chimeras for Spatiotemporally Resolved Protein Degradation In Vivo

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Publication Details

Journal
Angewandte Chemie International Edition
Published
2026-09-08
DOI
https://doi.org/10.1002/anie.2233329
Primary Topic
Click Chemistry and Applications
Type
article
Field-Weighted Citation Impact
0.00
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article

Click‐Activated Supramolecular Targeting Chimeras for Spatiotemporally Resolved Protein Degradation In Vivo

Yongsong Zhang, Ming Wang, Ji Liu, Tianyu Ma
Angewandte Chemie International Edition
Click Chemistry and Applications
article

Click‐Activated Supramolecular Targeting Chimeras for Spatiotemporally Resolved Protein Degradation In Vivo

Yongsong Zhang, Ming Wang, Ji Liu, Tianyu Ma
article en

Abstract

Targeted protein degradation (TPD) holds enormous therapeutic potential, yet spatiotemporally controlled, tissue-selective protein degradation remains challenging. Herein, we report Click-activated Supramolecular TArgeting Chimeras (ClSupTAC), a multimodular platform leveraging bioorthogonal chemistry to realize spatially and temporally resolved TPD in vivo. ClSupTAC follows a two-step "click-to-activate" paradigm: self-assembled, functionally dormant tissue-targeting supramolecular nanoparticles presenting protein-binding ligands and trans-cyclooctene (TCO) moieties are locally activated upon inverse electron-demand Diels-Alder (IEDDA) cycloaddition with tetrazine-E3 ubiquitin ligase recruiter conjugates. The IEDDA chemistry of ClSupTAC delivers accelerated addition reaction and protein degradation kinetics compared to Staudinger reaction-mediated activation of TPD. Moreover, ClSupTAC achieves rapid, selective degradation of pathogenic proteins in vitro and enables lung-targeted protein degradation in vivo. In acute lung injury models, ClSupTAC effectively alleviates pulmonary inflammation and recovers vascular barrier integrity. This study establishes ClSupTAC as a versatile and programmable platform for spatiotemporally precise protein regulation and targeted therapeutic intervention.

Angewandte Chemie International Edition
Chinese Academy of Sciences (CN), Beijing National Laboratory for Molecular Sciences (CN), University of Chinese Academy of Sciences (CN)
Openalex Percentile: Top 20%
Click Chemistry and Applications
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