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Yet many classical CIP platforms rely on ligands that may limit therapeutic translation owing to unfavorable biosafety profiles, off\u2010target activity, incomplete reversibility, dosing constraints, and potential immunogenicity of engineered components. This perspective highlights dietary small molecule\u2010 and OTC drug\u2010responsive CIP systems as emerging platforms for translational chemogenetic control. We focus on two complementary design strategies. One exploits nanobody\u2010derived binders against familiar small molecules, as exemplified by synthetic anti\u2010caffeine nanobody\u2010based systems. The other adapts naturally evolved ligand\u2010binding proteins through rational protein engineering, as illustrated by salicylate\u2010responsive platforms derived from plant salicylic acid (SA)\u2010binding receptors for reversible proximity control and aspirin\u2010responsive 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)\u2010guided protein engineering may expand this design space by enabling\n                    <jats:italic>de novo<\/jats:italic>\n                    construction and functional reprogramming of ligand\u2010responsive modules, leading to safer and clinically compatible proximity\u2010control systems.\n                  <\/jats:p>","DOI":"10.1002\/chem.71530","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T05:29:23Z","timestamp":1785821363000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Caffeine to Aspirin: Everyday Molecules as Triggers for Genetically Encoded Proximity Systems"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2788-5166","authenticated-orcid":false,"given":"Mingguang","family":"Cui","sequence":"first","affiliation":[{"name":"Center for Translational Cancer Research Institute of 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