A DNA‐Polymer Architecture for Targeted Multivalent PROTAC Delivery and Enhanced Intracellular Protein Degradation

Proteolysis‐targeting chimeras (PROTACs) enable the selective degradation of disease‐relevant proteins by recruiting E3 ubiquitin ligases; however, their therapeutic potential is often limited by insufficient intracellular availability and inadequate target selectivity. Here, we report a modular DNA‐polymer architecture that integrates target‐specific DNA aptamer with a multivalent polymer scaffold. By anchoring multiple PROTAC molecules to a single polymer backbone, this architecture enables targeted delivery while increasing the amount of PROTAC delivered per cellular uptake event. To validate this design, we developed a construct utilizing the AS1411 aptamer and a copolymer backbone bearing multiple ARV771 molecules, which achieved significantly enhanced BRD4 degradation compared with its monovalent counterparts. Furthermore, in vivo studies demonstrated that the system exhibits prolonged systemic circulation, sustained tumor accumulation, and significant inhibition of tumor growth. Collectively, this modular DNA‐polymer frame‐work establishes a versatile strategy for the precision delivery and functional enhancement of PROTAC‐based degraders across diverse therapeutic contexts.