From Caffeine to Aspirin: Everyday Molecules as Triggers for Genetically Encoded Proximity Systems

ABSTRACT

Chemically induced proximity (CIP) enables programmable control of gene expression, protein activity, cellular signaling, and engineered cell functions using small molecules. Yet many classical CIP platforms rely on ligands that may limit therapeutic translation owing to unfavorable biosafety profiles, off‐target activity, incomplete reversibility, dosing constraints, and potential immunogenicity of engineered components. This perspective highlights dietary small molecule‐ and OTC drug‐responsive CIP systems as emerging platforms for translational chemogenetic control. We focus on two complementary design strategies. One exploits nanobody‐derived binders against familiar small molecules, as exemplified by synthetic anti‐caffeine nanobody‐based systems. The other adapts naturally evolved ligand‐binding proteins through rational protein engineering, as illustrated by salicylate‐responsive platforms derived from plant salicylic acid (SA)‐binding receptors for reversible proximity control and aspirin‐responsive gene regulation. Together, these engineered systems demonstrate how familiar molecules such as caffeine, SA, and aspirin can be transformed into programmable biological inputs. We further discuss how artificial intelligence (AI)‐guided protein engineering may expand this design space by enabling de novo construction and functional reprogramming of ligand‐responsive modules, leading to safer and clinically compatible proximity‐control systems.