Chemically Induced Dimerization Systems: From FKBP/FRB Engineering to Expanded Biological Applications

Abstract The FKBP-based chemically induced dimerization (CID) technology is a fundamental tool for spatiotemporal precise modulation of protein functions in living cells, widely used in gene editing, protein function regulation, disease therapy, and drug development. However, its widespread application is limited by the inherent drawbacks including issues with immunosuppressive activity, stability, reversibility, and in vivo delivery. Recent years have seen remarkable progress in addressing these challenges: orthogonalization strategies eliminate immunosuppressive effects, fast-dissociating ligands and optogenetic systems enable reversible regulation, and protein engineering optimizes the FKBP/FRB domains to enhance stability and reduce immunogenicity. Moreover, integration with novel delivery technologies broadens its application scope greatly. This review summarizes the key optimization strategies and innovative applications of this technology in the cutting-edge biological research, aiming to reference the development of next-generation chemogenetic tools with higher precision, better safety, and greater application potential.