Beyond canonical PROTAC: biological targeted protein degradation (bioTPD)

Targeted protein degradation (TPD) is an emerging therapeutic strategy with the potential to modulate disease-associated proteins that have previously been considered undruggable, by employing the host destruction machinery. The exploration and discovery of cellular degradation pathways, including but not limited to proteasomes and lysosome pathways as well as their degraders, is an area of active research. Since the concept of proteolysis-targeting chimeras (PROTACs) was introduced in 2001, the paradigm of TPD has been greatly expanded and moved from academia to industry for clinical translation, with small-molecule TPD being particularly represented. As an indispensable part of TPD, biological TPD (bioTPD) technologies including peptide-, fusion protein-, antibody-, nucleic acid-based bioTPD and others have also emerged and undergone significant advancement in recent years, demonstrating unique and promising activities beyond those of conventional small-molecule TPD. In this review, we provide an overview of recent advances in bioTPD technologies, summarize their compositional features and potential applications, and briefly discuss their drawbacks. Moreover, we present some strategies to improve the delivery efficacy of bioTPD, addressing their challenges in further clinical development.