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Engineered receptors for soluble cellular communication and disease sensing. | LitMetric

AI Article Synopsis

  • Recent advancements in synthetic biology have struggled to create modular synthetic receptors that effectively respond to soluble ligands to activate specific cellular functions.
  • The novel synthetic intramembrane proteolysis receptor (SNIPR) was developed to be activated by both natural and artificial soluble ligands, utilizing a unique endocytic, pH-dependent cleavage mechanism.
  • SNIPR showcases potential therapeutic applications by targeting CAR T cells to solid tumors, reducing off-target effects, and allowing for the creation of synthetic signaling networks that operate independently of natural pathways.

Article 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 to date only receptors against cell surface targets have approached clinical translation. To address this gap, we developed a receptor architecture called synthetic intramembrane proteolysis receptor (SNIPR), that has the added ability to be activated by soluble ligands, both natural and synthetic, with remarkably 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 CAR T cells to solid tumors where soluble disease-associated factors are expressed, bypassing the major hurdle of on-target off-tumor toxicity in bystander organs. We further applied the SNIPR platform to engineer fully synthetic signaling networks between cells orthogonal to natural signaling 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.

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Source
http://dx.doi.org/10.1038/s41586-024-08366-0DOI Listing

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