Engineering Multicellular Inter‐Communication Systems Using a Synthetic Conformation Inducible Kinase Receptor

Abstract Synthetic multicellular inter‐communication systems are essential for understanding multicellular behaviors and developing cell‐based therapeutics. Synthetic receptors that allow programming of multicellular intercommunications through spatiotemporal control with light or chemical ligands are highly desirable but remain challenging. Here we propose a new strategy for designing multicellular inter‐communication systems using a synthetic conformation‐inducible kinase receptor (synCIKER). The synCIKER system is developed by engineering the extracellular domain of a tyrosine kinase receptor with domains responsive to inputs of chemical ligand, light or soluble protein, and rewiring the endogenous intracellular signaling pathways for prescribed transgene expression. The synCIKER system is demonstrated to sense these inputs, and generate customized secretory proteins for programming receiver cell behaviours such as surface receptor degradation and T cell‐mediated lysis in target cells. We also demonstrate the ability of synCIKER to construct cascade systems and reconfigure intelligent intercellular Boolean logic gates of OR, AND and INHIBIT for activating gene editing in receiver cells. The synCIKER platform is further exploited to modulate bi‐directional polarization of macrophages in a multi‐cellular system, highlighting its potential for designing synthetic intercellular communication systems for programming multicellular behaviors.