Beyond Purification: Evolving Roles of Fusion Tags in Biotechnology

Genetic fusion of a tag sequence to a target protein, or protein of interest (POI), is one of the most widely used technologies for recombinant expression. Tag-fusion proteins can enhance soluble expression, prolong half-life, increase binding avidity, and facilitate protein purification or refolding. In addition, tag-fusion proteins can be used to identify POI-binding partners through pull-down or immunoprecipitation assays. Beyond these classical applications, tags have evolved to serve as multifunctional tools, enabling real-time imaging, spatial localization, targeted delivery, and regulation of protein activity in living systems. Some engineered tags also allow conditional control, such as pH or ligand-dependent stabilization, thus expanding their utility in synthetic biology and therapeutic design. Here, we summarize protein-based and peptide-based tags, as well as methods for tag removal. While not fully comprehensive, this review aims to help researchers design suitable tag formats for specific goals.