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

ABSTRACT Targeted protein degradation (TPD) holds enormous therapeutic potential, yet spatiotemporally controlled, tissue‐selective protein degradation remains challenging. Herein, we report Cl ick‐activated Sup ramolecular TA rgeting C himeras ( 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.