Genetic code expansion for chemosensing and chemical actuation of biological functions

Abstract Genetic code expansion (GCE) enables site‐specific incorporation of noncanonical amino acids (ncAAs) that introduce chemical functionalities beyond the canonical amino acid set and provide programmable control over protein state and function. This review focuses on chemically triggered strategies that regulate protein activity through engineered ncAA reactivity. We summarize core mechanistic principles, including reaction‐driven control, reversible coordination and molecular binding, and spectroscopic readout strategies. We organize system architectures for chemosensing into direct and indirect interaction modes and discuss how ncAA‐encoded protein state transitions are converted into measurable signals. Chemical actuation strategies extend protein‐level control to higher‐order biological outcomes, including enzymatic activation, regulated proteolysis, gene editing, signaling network modulation, and cell fate control, thereby positioning GCE‐enabled chemical sensing and actuation as a general molecular approach that links defined chemical inputs to precise biological actions.