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Engineering synthetic RNA devices for cell control

Nature Reviews Genetics volume 23, pages 215–228 (2022)Cite this article

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Abstract

The versatility of RNA in sensing and interacting with small molecules, proteins and other nucleic acids while encoding genetic instructions for protein translation makes it a powerful substrate for engineering biological systems. RNA devices integrate cellular information sensing, processing and actuation of specific signals into defined functions and have yielded programmable biological systems and novel therapeutics of increasing sophistication. However, challenges centred on expanding the range of analytes that can be sensed and adding new mechanisms of action have hindered the full realization of the field’s promise. Here, we describe recent advances that address these limitations and point to a significant maturation of synthetic RNA-based devices.

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Fig. 1: RNA cellular functions.
Fig. 2: RNA devices enable diverse applications.
Fig. 3: Novel methods accelerate RNA sensor selection.
Fig. 4: Emerging mechanisms of RNA processing and cell control for novel RNA devices.

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Acknowledgements

The authors thank J. Payne, P. Srinivasan and B. Townshend for valuable feedback in the preparation of this Review. This work was supported by the National Institutes of Health (NIH) (grant to C.D.S.), National Science Foundation (NSF) (graduate fellowships to P.B.D. and M.K.) and Howard Hughes Medical Institute (HHMI) (Gilliam graduate fellowship to M.K.). C.D.S. is a Chan Zuckerberg Biohub investigator.

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  1. Department of Bioengineering, Stanford University, Stanford, CA, USA

    Peter B. Dykstra, Matias Kaplan & Christina D. Smolke

  2. Chan Zuckerberg Biohub, San Francisco, CA, USA

    Christina D. Smolke

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  1. Peter B. Dykstra
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  2. Matias Kaplan
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  3. Christina D. Smolke
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The authors contributed equally to all aspects of the article.

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Correspondence to Christina D. Smolke.

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Nature Reviews Genetics thanks James M. Carothers, James J. Collins and Hirohide Saito for their contribution to the peer review of this work.

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Glossary

Sensor

An element that can detect signals, including nucleic acid sequences, proteins, small molecules or non-biological stimuli such as temperature and light.

Actuator

An element that can control a process or event.

Gene-regulatory RNA elements

RNA elements that control expression of a gene.

RNA devices

Engineered genetically encoded RNA elements that combine sensing and actuation activities.

Riboswitches

Natural RNA elements that conditionally regulate gene expression in response to binding of a small molecule.

Aptamers

Nucleic acid sequences that can bind a particular ligand, such as a small molecule or protein.

Ribozyme switch

A type of riboswitch that uses a ribozyme, an RNA element that acts through cleaving RNA, to encode the actuation component.

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Dykstra, P.B., Kaplan, M. & Smolke, C.D. Engineering synthetic RNA devices for cell control. Nat Rev Genet 23, 215–228 (2022). https://doi.org/10.1038/s41576-021-00436-7

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