The ability to selectively eliminate disease-driving proteins — rather than merely inhibit them — represents one of the most consequential shifts in drug development over the past decade. Conventional small-molecule PROTACs (Proteolysis Targeting Chimeras) have dominated this space, but a biologics-based variant known as BioPROTACs is attracting serious scientific attention as a potentially more versatile and precise alternative for conditions ranging from cancer to neurodegeneration.
BioPROTACs replace the small-molecule binding warheads of traditional PROTACs with biological recognition elements — such as nanobodies, designed ankyrin repeat proteins (DARPins), or other protein-based binders — fused to E3 ubiquitin ligase recruitment domains. This architecture allows targeting of proteins previously considered undruggable by conventional small molecules, including intrinsically disordered proteins and transcription factors that lack well-defined binding pockets. The approach hijacks the cell's own ubiquitin-proteasome system to tag and destroy pathological proteins, achieving degradation rather than simple functional blockade. Published in Acta Pharmacologica Sinica, the review synthesizes current BioPROTAC design strategies, E3 ligase selection, and delivery challenges across multiple disease contexts.
This review arrives at a moment when the targeted protein degradation field is maturing rapidly — several small-molecule PROTACs are now in Phase II and III clinical trials for hematological malignancies, lending the broader degrader concept substantial clinical credibility. BioPROTACs, however, remain largely at preclinical stages, and their therapeutic translation faces distinct hurdles: biological cargo is harder to deliver intracellularly than small molecules, manufacturing complexity is higher, and immunogenicity remains an unresolved concern. That said, the precision they offer over intracellular target selection could be transformative for oncology and neurodegenerative disease, where aberrant protein accumulation is causal rather than correlative. This is a confirmatory and synthesizing contribution to an active field — valuable for mapping the landscape, though not itself a paradigm-shifting experimental discovery.