Self-Assembled Nanoparticles for Targeted Protein Degradation Using Hydrophobic Tag Through Hydrophobic Polymer

Targeted protein degradation (TPD) strategies offer a promising approach in drug development by selectively degrading disease-causing proteins, providing an advantage over small molecule inhibitors. However, small molecule-based degraders are rapidly excreted from the body due to their low water solubility and instability in the bloodstream, and they also have poor tumor specificity. Here, we developed hydrophobic polymer tagging nanoparticles, called ARL-PLA-SS-PEG NPs, which use a hydrophobic tagging strategy on oncogenic proteins. The platform was constructed by conjugating an androgen receptor (AR) ligand to a PLA-PEG block copolymer containing disulfide bonds. The targeted protein degradation of ARL-PLA-SS-PEG NPs operates in response to glutathione (GSH) in cancer cells, exposing the hydrophobic polymer due to nanoparticle collapse. The ARL-PLA effectively degrades the AR through two proteolytic pathways, namely the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP). The ARL-PLA-SS-PEG NPs have demonstrated their ability to inhibit tumors in in vivo models, highlighting their potential as a pioneering platform in targeted protein degradation.