BioPROTACs: a promising approach for targeted protein degradation.

Targeted protein degradation (TPD) has emerged as an important therapeutic strategy in recent years. Proteolysis-targeting chimeras (PROTACs) are among the most extensively studied TPD technologies that eliminate target proteins through a "degradation rather than inhibition" mechanism. This mechanism offers opportunities to target proteins that are difficult to modulate using conventional small-molecule inhibitors and may also help mitigate drug resistance. However, the development of small-molecule PROTACs remains constrained by challenges associated with druggability, target accessibility, E3 ubiquitin ligase availability, and clinical translation. BioPROTACs have subsequently emerged as an alternative degradation platform in which genetically encoded protein modules replace conventional small-molecule ligands while preserving the underlying degradation mechanism. Their molecular design enables broader target recognition, flexible E3 ligase recruitment, and improved molecular specificity. Their emerging applications span cancer, viral infections, and neurodegenerative diseases. This review summarizes the molecular mechanisms, recent advances, and emerging applications of bioPROTAC technology, evaluates the current technical challenges, discusses potential strategies to address these limitations, and highlights future directions that may facilitate its clinical translation.