Engineering a modular double-transmembrane synthetic receptor system for customizing cellular programs

Summary: Implementation of designer receptors in engineered cells confers them to sense a particular physiological or disease state and respond with user-defined programs. To expand the therapeutic application scope of engineered cells, synthetic receptors realized through different strategies are in great demand. Here, we develop a synthetic receptor system that exerts dual control by incorporating two transmembrane helices for the signal chain. Together with a sensor-actuator device with minimal background signals and a positive loop circuit, this receptor system can sensitively respond to extracellular protein signals. We demonstrate that this synthetic receptor system can be readily adapted to respond to various inputs, such as interleukin-1 (IL-1), programmed death ligand 1 (PD-L1), and HER2, and release customized outputs, including fluorescence signals and the therapeutic molecule IL-2. The robust signaling ability and generality of this receptor system promise it to be a useful tool in the field of cell engineering for fundamental research and translational applications.