Polymer-engineered PROTAC nanovehicles amplify synergistic effects with temozolomide by BRD4 degradation†

As the most aggressive primary brain tumor, glioblastoma (GBM) remains therapeutically challenging. Proteolysis-targeting chimeras (PROTACs), capable of degrading target proteins like BRD4, offer a promising strategy for GBM therapy. However, their clinical application is limited by poor solubility, stability, and bioavailability. This study systematically evaluates PLGA, PCL, and poly amino-acid based nanoparticles (NPs) for optimizing ARV-825, a BRD4-degrading PROTAC. This study compares the particle size, polydispersity index (PDI), and encapsulation efficiency of NPs prepared by different methods and carriers, explores the computer-simulated design of cyclic peptide carriers, and reveals the impact of PROTAC's molecular structure and action time on its toxicity. Furthermore, the delivery of ARV-825 using NPs achieves synergistic anti-tumor effects with temozolomide (TMZ) in GBM cells. These findings validate nanovehicles as a strategic solution for PROTAC limitations and provide a blueprint for translating catalytic degradation into clinically viable therapies against GBM.