Modular design of synthetic receptors for programmed gene regulation in cell therapies

Iowis Zhu, Raymond Liu, Julie M. Garcia, Axel Hyrenius-Wittsten, Dan I. Piraner, Josef Alavi, Divya V. Israni, Bin Liu, Ahmad S. Khalil, Kole T. Roybal

Research output: Contribution to journalArticlepeer-review


Synthetic biology has established powerful tools to precisely control cell function. Engineering these systems to meet clinical requirements has enormous medical implications. Here, we adopted a clinically driven design process to build receptors for the autonomous control of therapeutic cells. We examined the function of key domains involved in regulated intramembrane proteolysis and showed that systematic modular engineering can generate a class of receptors that we call synthetic intramembrane proteolysis receptors (SNIPRs) that have tunable sensing and transcriptional response abilities. We demonstrate the therapeutic potential of the receptor platform by engineering human primary T cells for multi-antigen recognition and production of dosed, bioactive payloads relevant to the treatment of disease. Our design framework enables the development of fully humanized and customizable transcriptional receptors for the programming of therapeutic cells suitable for clinical translation.

Original languageEnglish
Pages (from-to)1431-1443.e16
Issue number8
Publication statusPublished - 2022 Apr

Subject classification (UKÄ)

  • Cancer and Oncology

Free keywords

  • cancer immunotherapy
  • CAR-T cells
  • cell therapy
  • synNotch
  • synthetic biology


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