Design of Smart Antibody Mimetics with Photosensitive Switches

Abstract As two prominent examples of intracellular single‐domain antibodies or antibody mimetics derived from synthetic protein scaffolds, monobodies and nanobodies are gaining wide applications in cell biology, structural biology, synthetic immunology, and theranostics. Herein, a generally applicable method to engineer light‐controllable monobodies and nanobodies, designated as moonbody and sunbody, respectively, is introduced. These engineered antibody‐like modular domains enable rapid and reversible antibody–antigen recognition by utilizing light. By the paralleled insertion of two light‐oxygen‐voltage domain 2 modules into a single sunbody and the use of bivalent sunbodies, the range of dynamic changes of photoswitchable sunbodies is substantially enhanced. Furthermore, the use of moonbodies or sunbodies to precisely control protein degradation, gene transcription, and base editing by harnessing the power of light is demonstrated.