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

## TL;DR

This paper introduces a new method for targeted protein degradation using ultrasound and bioorthogonal chemistry to destroy proteins in hard-to-reach tissues with minimal side effects.

## Contribution

The novel SDPTAC platform enables noninvasive, deep-tissue protein degradation using ultrasound-activated chemistry without E3 ligase dependence.

## Key findings

- SDPTAC efficiently degrades nuclear, cytosolic, and membrane proteins in cells.
- The method achieved nearly complete tumor growth inhibition in vivo with low toxicity.
- ROS generation via sonosensitizer and tetrazine ligand assembly enables precise protein targeting.

## 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.

Bioorthogonal SDPTAC harnesses US‐responsive Ce6‐TCO and Tz ligands via IEDDA click chemistry to assemble degraders in situ, generating ROS that selectively eliminate nuclear, cytosolic, and membrane proteins, thereby suppressing deep‐seated tumors in vivo.