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Published on: June 6, 2020
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Engineered receptors for soluble cellular communication and disease sensing
Dan I Piraner1, Mohamad H Abedi2, Maria J Duran Gonzalez1
1Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
Nature
|November 14, 2024
Summary
Scientists developed a new synthetic receptor (SNIPR) that responds to soluble factors, enabling targeted cell therapy and synthetic biology. This breakthrough allows engineered cells to activate only in specific environments, enhancing safety and precision.
Area of Science:
- Synthetic biology
- Molecular engineering
- Cellular engineering
Background:
- Existing synthetic receptors primarily target cell-surface molecules, limiting therapeutic applications.
- A need exists for modular receptors that respond to soluble ligands for precise cellular control.
- Current engineered cell therapies face challenges with on-target, off-tumour toxicity.
Purpose of the Study:
- To adapt the synthetic intramembrane proteolysis receptor (SNIPR) architecture for soluble ligand activation.
- To engineer a robust synthetic receptor platform with low baseline activity and high fold activation.
- To demonstrate the therapeutic potential of soluble-ligand-activated SNIPRs in cancer and synthetic biology.
Main Methods:
- Modification of the SNIPR architecture for soluble ligand recognition.
- Utilizing an endocytic, pH-dependent cleavage mechanism for receptor activation.
- Application of the SNIPR platform to engineer chimeric antigen receptor (CAR) T cells for targeted tumour therapy.
- Development of orthogonal synthetic signaling networks between cells.
Main Results:
- The adapted SNIPR platform demonstrates activation by both natural and synthetic soluble factors.
- Achieved low baseline receptor activity and high fold activation.
- Successfully localized CAR T cell activity to solid tumours expressing soluble disease-associated factors.
- Engineered fully synthetic, orthogonal cell-to-cell signaling networks.
Conclusions:
- The SNIPR platform provides a modular solution for soluble ligand detection and cellular response.
- This technology enables targeted cell therapies, mitigating off-target toxicities.
- The SNIPR system expands the capabilities of synthetic biology for cellular communication and environmental interaction.
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