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Non-model bacteria as platforms for endogenous gene expression in synthetic biology

Nature Reviews Bioengineering volume 4, pages 67–81 (2026)Cite this article

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Abstract

Microbial synthetic biology seeks to engineer bacterial genomes for industrial and biomedical applications, typically by applying heterologous gene expression in well-characterized model organisms, such as Escherichia coli. However, heterologous gene expression might cause metabolic disruptions, thereby impacting production efficiency and yield. In this Review, we highlight non-model organisms, such as Lacticaseibacillus and pseudomonads, for endogenous compound production, taking advantage of their evolutionary optimization for the production of certain metabolites and proteins. We first outline key limitations of heterologous production and then examine endogenous production pathways in non-model organisms for biotechnological and therapeutic applications. In particular, multi-omics approaches enable the discovery and characterization of these organisms, and phage-based genome refactoring enhances genome engineering capabilities. Finally, we outline key bottlenecks in the application of non-model organisms in biotechnology, including scale-up, costs and safety.

Key points

  • Chassis diversification is essential to unlock the full potential of microbial synthetic biology.

  • Native producers have an evolutionary advantage over heterologous expression hosts, which can be leveraged for biotechnological applications.

  • Multi-omics techniques enable the characterization of non-model organisms to become the next generation of synthetic biology chassis.

  • Bacteriophage genomes are valuable sources for the discovery of synthetic biology tools to modify gene expression in non-model organisms.

  • The switch towards endogenous gene expression can improve market adoption for the second generation of microbial cell factories.

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Fig. 1: Heterologous and endogenous gene expression in biotechnology.
Fig. 2: Omics technologies guiding the transition from isolation to microbial cell factories.
Fig. 3: Pipeline to identify and test phage-derived regulatory elements.

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Acknowledgements

J.P. holds a predoctoral SB scholarship from FWO (grant no. 1S18723N). M.B., M.D.M. and R.L. are supported by a grant from the Special Research Fund (grant no. iBOF/21/092). J.M. and R.L. are supported by a grant from FWO (grant no. G044624N).

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Authors and Affiliations

  1. Laboratory of Gene Technology, Department of Biosystems, KU Leuven, Leuven, Belgium

    Jorien Poppeliers, Maarten Boon & Rob Lavigne

  2. Laboratory for Biomolecular Discovery and Engineering, Department of Biology, KU Leuven, Leuven, Belgium

    Jorien Poppeliers & Joleen Masschelein

  3. Metabolic Engineering of Microorganisms group, Department of Biotechnology, UGent, Ghent, Belgium

    Marjan De Mey

  4. Center for Microbiology, VIB-KU Leuven, Leuven, Belgium

    Joleen Masschelein

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Poppeliers, J., Boon, M., De Mey, M. et al. Non-model bacteria as platforms for endogenous gene expression in synthetic biology. Nat Rev Bioeng 4, 67–81 (2026). https://doi.org/10.1038/s44222-025-00354-x

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