The Polymer Society of Korea

Abstract

Targeted protein degradation (TPD) enables selective elimination of pathogenic proteins, offering advantages over occupancy-driven inhibitors that are prone to resistance. Clinical translation is hindered by poor aqueous solubility, unfavorable pharmacokinetics, and limited tumor selectivity of current TPD agents. We report a self-delivering polymeric nano-degrader that embeds the degradative moiety into a nanomedicine via hydrophobic polymer tagging. An androgen receptor ligand (ARL) is conjugated to polylactic acid (PLA) and PEGylated through a glutathione-responsive cleavable linker to form micelles. These micelles remain stable during circulation but disassemble under reductive intracellular conditions, exposing the hydrophobic polymeric degrader. The platform promotes androgen receptor degradation in vitro, enhances tumor accumulation, and suppresses tumor growth in vivo, supporting broad adaptability.