Bioorthogonal Sonodynamic Plug‐and‐Play Targeting Chimeras (SDPTAC) for Precise Targeted Protein Degradation

ABSTRACT Targeted protein degradation (TPD) offers powerful therapeutic opportunities but is limited by poor tissue penetration and E3 ligase dependence. Herein, we develop Sonodynamic Plug‐and‐Play Targeting Chimeras (SDPTAC), an ultrasound (US)‐activated, bioorthogonal strategy for in situ protein degradation. SDPTAC assembles via an inverse electron‐demand Diels–Alder (IEDDA) click reaction between a sonosensitizer and tetrazine‐tagged ligands, generating reactive oxygen species (ROS) upon US to degrade bound proteins. This modular platform enabled efficient degradation of nuclear (bromodomain‐containing protein 4, BRD4), cytosolic (nicotinamide phosphoribosyl transferase, NAMPT), and membrane (discoidin domain receptor 1, DDR1) targets, suppressed oncogenic signaling, and achieved nearly complete tumor growth inhibition in vivo with negligible toxicity. SDPTAC thus establishes a versatile, deep‐penetrating, and clinically translatable approach for noninvasive protein modulation.