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  • Review Article
  • Published:

Synthetic macromolecular switches for precision control of therapeutic cell functions

Nature Reviews Bioengineering volume 2, pages 1005–1022 (2024)Cite this article

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Abstract

Cells rely on complex molecular networks to perceive and process external and internal signals into tailored responses. These cellular abilities can be augmented and modified by integrating artificial gene circuitry for the engineering of cell-based therapeutics. In this Review, we outline the engineering principles that govern the design of synthetic gene networks, highlighting how the sensitivity, detection range and specificity of synthetic gene networks can be optimized for in vivo functionality. In particular, we examine synthetic molecular modules, including transcriptionally regulated, translationally regulated and post-translationally regulated circuits, that enable tailored adjustments in therapeutic cell functions based on dynamic disease-state cues, or that can be remotely controlled using clinically compatible external molecular or physical signals. Furthermore, we explore the potential of multi-input regulatable logic-gated programs to enhance the efficacy and safety of engineered cell immunotherapies for cancer treatment, and highlight the application of synthetic gene circuits for gene therapy and the design of therapeutic microbes. Finally, we examine how synthetic-biology-inspired therapies may benefit from evolving genome engineering technologies and synergy with artificial intelligence.

Key points

  • Synthetic macromolecular switches responding to external or endogenous signals at the DNA, RNA or protein level offer promising tools for developing safe and effective therapeutic cells.

  • Consideration of tradeoffs inherent to each regulatory mode, including dynamic ranges, response times, genetic footprint and component sources, is crucial for their optimal therapeutic application.

  • Synthetic transcriptional systems can be integrated in cancer gene and cell therapy products, and translational and post-translational switches are being explored in preclinical studies.

  • Machine learning models, trained on high-quality datasets, can aid in the design and optimization of synthetic macromolecular circuits to meet clinical requirements while reducing the time and cost of development.

  • To aid the clinical translation of large circuits integrating extracellularly controlled logical operations, gene transfer methods for ex vivo or in vivo cell engineering must be improved.

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Fig. 1: Programming transcriptional regulatory networks for responsiveness to molecular or physical signals.
Fig. 2: Programming translational regulatory networks for responsiveness to external signals.
Fig. 3: Applications of post-translationally regulated systems.
Fig. 4: Regulatable engineered cells targeting cancer.
Fig. 5: Leveraging artificial intelligence to advance synthetic-biology-inspired therapies.

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Acknowledgements

The authors disclose support for this work from the European Research Council (grant number 785800) and from the Swiss National Science Foundation (NCCR Molecular Systems Engineering).

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  1. Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland

    Ana Palma Teixeira & Martin Fussenegger

  2. Faculty of Science, University of Basel, Basel, Switzerland

    Martin Fussenegger

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Teixeira, A.P., Fussenegger, M. Synthetic macromolecular switches for precision control of therapeutic cell functions. Nat Rev Bioeng 2, 1005–1022 (2024). https://doi.org/10.1038/s44222-024-00235-9

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