Engineered receptors for soluble cellular communication and disease sensing
成果类型：
Article
署名作者：
Piraner, Dan I.; Abedi, Mohamad H.; Duran Gonzalez, Maria J.; Chazin-Gray, Adam; Lin, Annie; Zhu, Iowis; Ravindran, Pavithran T.; Schlichthaerle, Thomas; Huang, Buwei; Bearchild, Tyler H.; Lee, David; Wyman, Sarah; Jun, Young-wook; Baker, David; Roybal, Kole T.
署名单位：
University of California System; University of California San Francisco; University of Washington; University of Washington Seattle; University of California System; University of California San Francisco; University of California System; University of California Berkeley; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute; University of Washington; University of Washington Seattle; Chan Zuckerberg Initiative (CZI); University of Pennsylvania
刊物名称：
Nature
ISSN/ISSBN：
0028-1475
DOI：
10.1038/s41586-024-08366-0
发表日期：
2025-02-20
关键词：
摘要：
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.