Engineering a Reconfigurable Transmembrane Receptor Enables Logic-Controlled Signal Translocation.

Transmembrane receptors relay extracellular cues into intracellular responses through reconfigurable conformational changes, yet engineering synthetic systems that emulate receptor-like signal translocation with programmable control remains challenging. 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─H+ and ATP─through 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 >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.