Reprogramming chemically induced dimerization systems with genetically encoded nanobodies

Abstract

Chemically induced proximity (CIP) systems harness small molecules to control protein-protein interactions, thereby enabling remote control over physiological processes and advancing the development of intelligent therapeutics. While substantial efforts have focused on developing new chemical inducers for tailored CIP applications, repurposing established systems to confer novel functions remains a highly cost-effective and efficient strategy. In this study, we employed genetically encoded nanobodies to overcome key bottlenecks of two widely used CIP systems in specific biological contexts. By incorporating the bivalent COSMO module and UniRapR into an anti-mCherry nanobody, we reprogrammed the homodimeric COSMO system into a caffeine-inducible heterodimerization system and transformed the classic rapamycin-dependent ON switch into an OFF switch, thereby conferring new functionality of the existing chemogenetic toolkit and expanding the repertoire of CIP technologies.