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

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.