Recent advances in the development of tag-targeted protein degradation systems

Targeted protein degradation (TPD) has emerged as an important strategy for regulating protein abundance and exploring therapeutic targets. However, for many candidate targets, the lack of suitable small-molecule ligands makes it difficult to assess their degradability and the biological consequences of protein depletion before developing target-specific degraders. Tag-targeted protein degradation (tTPD) provides an alternative approach by introducing a specific tag into the protein of interest and using tag-directed degradation systems to achieve controlled protein depletion. Over the past two decades, a variety of ligand-based and nanobody-based tTPD systems have been developed for protein function studies and target validation. In this review, we summarise the major tTPD systems reported to date, focusing on their design, degradation mechanisms, representative applications, advantages, and limitations. We further discuss the selection of appropriate tTPD systems, potential strategies for developing new tTPD tools, and opportunities to expand their applications.