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Aging-dependent evolving electrochemical potentials of biomolecular condensates regulate their physicochemical activities

Nature Chemistry (2025)Cite this article

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Abstract

A passive consequence of macromolecular condensation is the establishment of an ion concentration gradient between the dilute and dense phases, which in turn governs distinct electrochemical properties of condensates. However, the mechanisms that regulate the electrochemical equilibrium of condensates and their impacts on emergent physicochemical functions remain unknown. Here we demonstrate that the electrochemical environments and the physical and chemical activities of biomolecular condensates, dependent on the electrochemical potential of condensates, are regulated by aging-associated intermolecular interactions and interfacial effects. Our findings reveal that enhanced dense-phase interactions during condensate maturation continuously modulate the ion distribution between the two phases. Moreover, modulating the interfacial regions of condensates can affect the apparent pH within the condensates. To directly probe the interphase and interfacial electric potentials of condensates, we have designed and implemented electrochemical potentiometry and second harmonic generation-based approaches. Our results suggest that the non-equilibrium nature of biomolecular condensates might play a crucial role in modulating the electrochemical activities of living systems.

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Fig. 1: The aging-dependent internal pH transition of biomolecular condensates.
Fig. 2: The aging-dependent interfacial structure of condensates affects condensate pH.
Fig. 3: Analysing the interphase electric potential with electrochemical potentiometry.
Fig. 4: Evaluation of aging-dependent surface potentials of condensates with SHG.
Fig. 5: The interfacial potential of condensates modulates the electrochemical and physical functions of condensates.

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Acknowledgements

We acknowledge experimental support from the Center for Biomolecular Condensates and the Biology Imaging Facility of Washington University in St Louis. We appreciate helpful discussions with Z.-G. Wang’s group at California Institute of Technology. We acknowledge funding support from the McKelvy School of Engineering of Washington University in St Louis. Part of this work was supported by the Air Force Office of Scientific Research (FA9550-21-1-0170 to R.N.Z.).

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  1. These authors contributed equally: Wen Yu, Xiao Guo, Yu Xia, Yuefeng Ma.

Authors and Affiliations

  1. Department of Biomedical Engineering, Washington University in St Louis, St Louis, MO, USA

    Wen Yu, Xiao Guo, Yuefeng Ma, Zhongli Tong, Leshan Yang & Yifan Dai

  2. Department of Chemistry, Stanford University, Stanford, CA, USA

    Yu Xia, Xiaowei Song & Richard N. Zare

  3. Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA

    Guosong Hong

  4. Center for Biomolecular Condensates, Washington University in St Louis, St Louis, MO, USA

    Yifan Dai

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Contributions

Y.D. generated the idea for this article. Y.D., G.H. and R.N.Z. devised the study. W.Y., X.G., Y.X., Y.M., Z.T., L.Y. and X.S. conducted the experiments. X.G., Y.X., W.Y., Y.M., L.Y. and Z.T. analysed the data. Y.D., G.H. and R.N.Z. wrote the paper, and all authors commented on the paper.

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Correspondence to Richard N. Zare, Guosong Hong or Yifan Dai.

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Nature Chemistry thanks Ellen Adams, Ben Erne, Drgomir Milovanovic, Mario Tagliazucchi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Texts 1–3, Figs. 1–7, Table 1 and References.

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Source Data Fig. 1

Interior apparent pH of condensates at different time points.

Source Data Fig. 2

Different categories of condensates or treatments to condensates and their corresponding interior apparent pH.

Source Data Fig. 3

Electrochemical quantification of interphase electric potential difference between phases for different salt conditions and aging process.

Source Data Fig. 4

SHG signal of condensates under different salt conditions and aging time points and derived surface potentials of condensates at different ages.

Source Data Fig. 5

Analysis of electrochemical activity, partitioning functions of charged molecules and the growth of amyloid based on condensates with different ages.

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Yu, W., Guo, X., Xia, Y. et al. Aging-dependent evolving electrochemical potentials of biomolecular condensates regulate their physicochemical activities. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01762-7

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