Engineered receptors for soluble cellular communication and disease sensing

Dan I. Piraner, Mohamad H. Abedi, Maria J. Duran Gonzalez, Adam Chazin-Gray, Annie Lin, Iowis Zhu, Pavithran T. Ravindran, Thomas Schlichthaerle, Buwei Huang, Tyler H. Bearchild, David Lee, Sarah Wyman, Young-wook Jun, David Baker () and Kole T. Roybal ()
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Dan I. Piraner: University of California San Francisco
Mohamad H. Abedi: University of Washington
Maria J. Duran Gonzalez: University of California San Francisco
Adam Chazin-Gray: University of Washington
Annie Lin: University of California San Francisco and University of California Berkeley
Iowis Zhu: University of California San Francisco
Pavithran T. Ravindran: University of California San Francisco
Thomas Schlichthaerle: University of Washington
Buwei Huang: University of Washington
Tyler H. Bearchild: University of California San Francisco
David Lee: University of Washington
Sarah Wyman: University of California San Francisco
Young-wook Jun: University of California San Francisco
David Baker: University of Washington
Kole T. Roybal: University of California San Francisco

Nature, 2025, vol. 638, issue 8051, 805-813

Abstract: Abstract Despite recent advances in mammalian synthetic biology, there remains a lack of modular synthetic receptors that can robustly respond to soluble ligands and, in turn, activate bespoke cellular functions. Such receptors would have extensive clinical potential to regulate the activity of engineered therapeutic cells, but so far only receptors against cell-surface targets have approached clinical translation1. To address this gap, here we adapt a receptor architecture called the synthetic intramembrane proteolysis receptor (SNIPR) for activation by soluble ligands. Our SNIPR platform can be activated by both natural and synthetic soluble factors, with notably low baseline activity and high fold activation, through an endocytic, pH-dependent cleavage mechanism. We demonstrate the therapeutic capabilities of the receptor platform by localizing the activity of chimeric antigen receptor (CAR) T cells to solid tumours in which soluble disease-associated factors are expressed, bypassing the major hurdle of on-target off-tumour toxicity in bystander organs. We further apply the SNIPR platform to engineer fully synthetic signalling networks between cells orthogonal to natural signalling pathways, expanding the scope of synthetic biology. Our design framework enables cellular communication and environmental interactions, extending the capabilities of synthetic cellular networking in clinical and research contexts.

Date: 2025
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DOI: 10.1038/s41586-024-08366-0

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