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Here, we engineer a reconfigurable transmembrane receptor that enables logic-controlled signal translocation across lipid membranes. The receptor is constructed from an oriented Y-shaped triplex DNA architecture that inserts directionally into the plasma membrane via dual cholesterol anchors and integrates two environmental inputs\u2500H+ and ATP\u2500through an i-motif and an aptamer module. Under dual-input conditions, cooperative duplex-to-triplex switching triggers reconfigurable structural rearrangement and drives transmembrane relocation of a signaling strand from the outer to the inner membrane leaflet. This receptor-mediated signal translocation converts extracellular chemical cues into spatially defined intracellular activation. The repositioned strand serves as a modular intracellular effector that can be functionalized to implement programmable reactions, including bioorthogonal catalysis and light-triggered photocatalysis at the membrane interface. Importantly, endogenous tumor-microenvironmental cues trigger receptor reconfiguration and signal translocation in 3D tumor spheroids and in vivo, enabling logic-gated intracellular photocatalysis and &amp;gt;85% tumor growth inhibition in xenograft models. By coupling logic-gated reconfigurable switching with directional transmembrane signal propagation, this work establishes an engineered transmembrane receptor for programmable intracellular activation and provides a general strategy for synthetic signal translocation in living systems.<\/jats:p>","DOI":"10.1021\/jacs.6c19185","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T16:01:16Z","timestamp":1791648076000},"page":"45266-45279","source":"Crossref","is-referenced-by-count":0,"title":["Engineering a Reconfigurable\nTransmembrane Receptor\nEnables Logic-Controlled Signal Translocation"],"prefix":"10.1021","volume":"148","author":[{"given":"Hui","family":"Chen","sequence":"first","affiliation":[{"name":"Hunan Normal University , , ,","place":["Changsha, P. R. China, 410081"]},{"name":"University of South China , , ,","place":["Hengyang, P. R. China, 421001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu-Pan","family":"Yang","sequence":"additional","affiliation":[{"name":"University of South China , , ,","place":["Hengyang, P. R. China, 421001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7670-8951","authenticated-orcid":true,"given":"Zhen","family":"Zou","sequence":"additional","affiliation":[{"name":"Hunan Normal University , , ,","place":["Changsha, P. R. China, 410081"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2890-682X","authenticated-orcid":true,"given":"Jin","family":"Huang","sequence":"additional","affiliation":[{"name":"Hunan University , , ,","place":["Changsha, P. R. China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1747-5398","authenticated-orcid":true,"given":"Jing","family":"Zheng","sequence":"additional","affiliation":[{"name":"Hunan University , , ,","place":["Changsha, P. R. China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9390-4938","authenticated-orcid":true,"given":"Kemin","family":"Wang","sequence":"additional","affiliation":[{"name":"Hunan University , , ,","place":["Changsha, P. R. China, 410082"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8282-4078","authenticated-orcid":true,"given":"Jianbo","family":"Liu","sequence":"additional","affiliation":[{"name":"Hunan Normal University , , ,","place":["Changsha, P. R. China, 410081"]},{"name":"Hunan University , , ,","place":["Changsha, P. R. 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Rev.\nChem."},{"issue":"37","key":"2026102111083532400_cit27","doi-asserted-by":"publisher","first-page":"33643","DOI":"10.1021\/jacs.5c09188","article-title":"DNA flipping as facile mechanism for transmembrane\nsignaling in synthetic cells","volume":"147","author":"Baranda Pellejero","year":"2025","journal-title":"J. Am. Chem. Soc."},{"issue":"1","key":"2026102111083532400_cit28","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04821-5","article-title":"A synthetic enzyme built from DNA\nflips 107 lipids per second in biological membranes","volume":"9","author":"Ohmann","year":"2018","journal-title":"Nat. Commun."},{"issue":"19","key":"2026102111083532400_cit29","doi-asserted-by":"publisher","first-page":"7358","DOI":"10.1021\/jacs.1c00166","article-title":"Cations regulate membrane attachment\nand functionality of DNA nanostructures","volume":"143","author":"Morzy","year":"2021","journal-title":"J.\nAm. Chem. 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Mater."},{"issue":"5","key":"2026102111083532400_cit50","doi-asserted-by":"publisher","first-page":"5778","DOI":"10.1021\/acsnano.9b01324","article-title":"DNA logic\noperations in living cells\nutilizing lysosome-recognizing framework nucleic acid nanodevices\nfor subcellular imaging","volume":"13","author":"Du","year":"2019","journal-title":"ACS Nano"},{"issue":"37","key":"2026102111083532400_cit51","doi-asserted-by":"publisher","first-page":"15084","DOI":"10.1021\/jacs.1c04925","article-title":"Rapid and\nspecific imaging of extracellular signaling molecule adenosine triphosphate\nwith a self-phosphorylating DNAzyme","volume":"143","author":"Zhao","year":"2021","journal-title":"J. Am.\nChem. Soc."},{"issue":"15","key":"2026102111083532400_cit52","doi-asserted-by":"publisher","first-page":"6099","DOI":"10.1002\/anie.201916432","article-title":"Environment-recognizing DNA-computation circuits for the intracellular\ntransport of molecular payloads for mRNA imaging","volume":"59","author":"Wang","year":"2020","journal-title":"Angew. Chem., Int. Ed."},{"issue":"42","key":"2026102111083532400_cit53","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202002629","article-title":"ATP-responsive and\nATP-fueled self-assembling systems\nand materials","volume":"32","author":"Deng","year":"2020","journal-title":"Adv. Mater."},{"issue":"32","key":"2026102111083532400_cit54","doi-asserted-by":"publisher","first-page":"10226","DOI":"10.1002\/anie.201806155","article-title":"A DNA-mediated chemically induced\ndimerization (D-CID) nanodevice for nongenetic receptor engineering\nto control cell behavior","volume":"57","author":"Li","year":"2018","journal-title":"Angew. 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