Synthetic biology has established powerful tools for precise and complex control of cellular function. Engineering such systems to meet clinical requirements remains challenging but has enormous implications for the successful treatment of human disease. Here, we adopted a clinically driven design process to build and test receptors for the autonomous control of therapeutic cells. We examined the function of the key domains of regulated-intramembrane-proteolysis (RIP) receptors and show that modular assembly and engineering of the component domains can generate a suite of compact and SyNthetic Intramembrane Proteolysis Receptors (SNIPRs) with tunable sensing and transcriptional response abilities in T cells. We demonstrate the potential transformative utility of this new receptor platform by engineering cells for multi-antigen recognition and delivery of dosed, bioactive payloads relevant to the treatment of disease. Our design framework enables the development of a fully customizable transcriptional receptors platform for the programming of therapeutic cells suitable for clinical translation.
