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Abiotic lipid metabolism enables membrane plasticity in artificial cells

Nature Chemistry volume 17, pages 799–807 (2025)Cite this article

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Abstract

The plasticity of living cell membranes relies on complex metabolic networks fueled by cellular energy. These metabolic processes exert direct control over membrane properties such as lipid composition and morphological plasticity, which are essential for cellular functions. Despite notable progress in the development of artificial systems mimicking natural membranes, the realization of synthetic membranes capable of sustaining metabolic cycles remains a challenge. Here we present an abiotic phospholipid metabolic network that generates and maintains dynamic artificial cell membranes. Chemical coupling agents drive the in situ synthesis of transiently stable non-canonical phospholipids, leading to the formation and maintenance of phospholipid membranes. We find that phospholipid metabolic cycles can drive lipid self-selection, favouring the enrichment of specific lipid species. Moreover, we demonstrate that controlling lipid metabolism can induce reversible membrane phase transitions, facilitating lipid mixing between distinct populations of artificial membranes. Our work demonstrates that a simple lipid metabolic network can drive dynamic behaviour in artificial membranes, offering insights into mechanisms for engineering functional synthetic compartments.

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Fig. 1: Establishing an abiotic phospholipid metabolic network.
Fig. 2: Characterization of the synthetic phospholipid metabolic network.
Fig. 3: Enrichment of specific phospholipids during synthetic metabolism.
Fig. 4: Membrane phase transitions governed by a phospholipid metabolic network.

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All of the data that support the findings of this study are available in the main text or Supplementary Information. Source data are provided with this paper.

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Acknowledgements

We acknowledge the facilities as well as the scientific and technical assistance of the staff of the cryoEM facility at UC San Diego. K. A. Podolsky is acknowledged for her contribution to the preparation of the figures. This work was funded by the National Science Foundation (CHE-2304664). R.J.B. thanks the MCIN/AEI/10.13039/501100011033 and ERDF A way of making Europe (PID2021-128113NA-I100), as well as the Consellería de Cultura, Educación e Universidade da Xunta de Galicia (ED431F 2024/07 and ED431B 2023/60) for funding. R.J.B. also thanks the MCIN/AEI/10.13039/501100011033 and ESF Investing in your future for his Ramón y Cajal contract (RYC2020-030065-I). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Alessandro Fracassi, Andrés Seoane.

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA

    Alessandro Fracassi, Andrés Seoane, Hong-Guen Lee, Alexander Harjung & Neal K. Devaraj

  2. Bioinspired Nanochemistry (BioNanoChem) Group, CICA Centro Interdisciplinar de Química e Bioloxía, Universidade da Coruña, A Coruña, Spain

    Roberto J. Brea

Authors
  1. Alessandro Fracassi
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Contributions

A.F., A.S., R.J.B. and N.K.D. conceived the idea. A.F., A.S., R.J.B., H.-G.L. and A.H. synthesized the organic molecules, characterized the lipid assemblies and performed all the experiments presented in this paper. A.F., A.S., R.J.B. and N.K.D. analysed and interpreted the results. A.F., A.S., R.J.B. and N.K.D. wrote and reviewed the paper.

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Correspondence to Neal K. Devaraj.

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Nature Chemistry thanks Marten Exterkate, Roger Rubio-Sanchez and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Fracassi, A., Seoane, A., Brea, R.J. et al. Abiotic lipid metabolism enables membrane plasticity in artificial cells. Nat. Chem. 17, 799–807 (2025). https://doi.org/10.1038/s41557-025-01829-5

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