Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Universal membranization of synthetic coacervates and biomolecular condensates towards ultrastability and spontaneous emulsification

Nature Chemistry volume 17, pages 911–923 (2025)Cite this article

Subjects

Abstract

Membranization of membraneless coacervates and condensates is emerging as a promising strategy to resolve their inherent susceptibility to fusion, ripening and environmental variations. Yet current membranization agents by design are largely limited to a subclass or a specific kind of coacervate or condensate systems. Here we develop a library of condensate-amphiphilic block polymers that can efficiently form a polymeric layer on the droplet interface for a wide spectrum of synthetic coacervates and biomolecular condensates. Condensate-amphiphilic block polymers are designed with a condenophilic block firmly anchored to the condensed phase, a condenophobic block extended to the dilute phase and a self-association block to promote membrane formation. Critical to our design is the condenophilic block of phenylboronic acid and amidoamine that target the disparate chemistry of condensed droplets via multivalent affinities. The condensate-amphiphilic block polymer membranes render the droplets mechanically robust against fusion, regulate interfacial properties such as permeability and stiffness, and substantially improve droplet tolerance to challenging conditions of temperature, salinity, pH and organic solvents.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Modular design of CAPs for condensate membranization.
Fig. 2: Vast disparity of the 15 selected condensate systems (COND1 to COND15) in terms of chemical compositions and physical properties.
Fig. 3: Comparison of stabilization performances between different stabilizers.
Fig. 4: CAP membranization and its impact on intradroplet and interfacial dynamics.
Fig. 5: Mechanical stability of membranized condensates.
Fig. 6: Spontaneous emulsification of COND1@CAP15 droplets.

Similar content being viewed by others

Data availability

The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information files. Source data can be found in files associated with this paper and in the figshare repository at https://doi.org/10.6084/m9.figshare.28069118 (ref. 72). All the data are also available from the corresponding author on request. Source data are provided with this paper.

References

  1. Spruijt, E. Open questions on liquid–liquid phase separation. Commun. Chem. 6, 23 (2023).

    PubMed  PubMed Central  Google Scholar 

  2. Booij, H. L. & Bungenberg de Jong, H. G. Biocolloids and Their Interactions (Springer, 1956).

  3. Lin, Z., Beneyton, T., Baret, J. C. & Martin, N. Coacervate droplets for synthetic cells. Small Methods 7, e2300496 (2023).

    PubMed  Google Scholar 

  4. Brangwynne, C. P. et al. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 324, 1729–1732 (2009).

    CAS  PubMed  Google Scholar 

  5. Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18, 285–298 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Shin, Y. & Brangwynne, C. P. Liquid phase condensation in cell physiology and disease. Science 357, eaaf4382 (2017).

    PubMed  Google Scholar 

  7. Yewdall, N. A., André, A. A. M., Lu, T. & Spruijt, E. Coacervates as models of membraneless organelles. Curr. Opin. Colloid Interface Sci. 52, 101416 (2021).

    CAS  Google Scholar 

  8. Xu, C., Martin, N., Li, M. & Mann, S. Living material assembly of bacteriogenic protocells. Nature 609, 1029–1037 (2022).

    CAS  PubMed  Google Scholar 

  9. Timilsena, Y. P., Akanbi, T. O., Khalid, N., Adhikari, B. & Barrow, C. J. Complex coacervation: principles, mechanisms and applications in microencapsulation. Int. J. Biol. Macromol. 121, 1276–1286 (2019).

    CAS  PubMed  Google Scholar 

  10. Su, Q., Mehta, S. & Zhang, J. Liquid–liquid phase separation: orchestrating cell signaling through time and space. Mol. Cell 81, 4137–4146 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Brangwynne, C. P., Tompa, P. & Pappu, R. V. Polymer physics of intracellular phase transitions. Nat. Phys. 11, 899–904 (2015).

    CAS  Google Scholar 

  12. Kilgore, H. R. & Young, R. A. Learning the chemical grammar of biomolecular condensates. Nat. Chem. Biol. 18, 1298–1306 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang, S. et al. Steering coacervation by a pair of broad-spectrum regulators. ACS Nano 13, 2420–2426 (2019).

    CAS  PubMed  Google Scholar 

  14. Chen, X. et al. Optothermally programmable liquids with spatiotemporal precision and functional complexity. Adv. Mater. 34, e2205563 (2022).

    PubMed  Google Scholar 

  15. Zhao, P. et al. Nanoparticle-assembled vacuolated coacervates control macromolecule spatiotemporal distribution to provide a stable segregated cell microenvironment. Adv. Mater. 33, e2007209 (2021).

    PubMed  Google Scholar 

  16. Lu, T., Javed, S., Bonfio, C. & Spruijt, E. Interfacing coacervates with membranes: from artificial organelles and hybrid protocells to intracellular delivery. Small Methods 7, e2300294 (2023).

    PubMed  Google Scholar 

  17. Gao, N. & Mann, S. Membranized coacervate microdroplets: from versatile protocell models to cytomimetic materials. Acc. Chem. Res. 56, 297–307 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Li, M., Harbron, R. L., Weaver, J. V., Binks, B. P. & Mann, S. Electrostatically gated membrane permeability in inorganic protocells. Nat. Chem. 5, 529–536 (2013).

    CAS  PubMed  Google Scholar 

  19. Dora Tang, T. Y. et al. Fatty acid membrane assembly on coacervate microdroplets as a step towards a hybrid protocell model. Nat. Chem. 6, 527–533 (2014).

    CAS  PubMed  Google Scholar 

  20. Mason, A. F., Buddingh, B. C., Williams, D. S. & van Hest, J. C. M. Hierarchical self-assembly of a copolymer-stabilized coacervate protocell. J. Am. Chem. Soc. 139, 17309–17312 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhao, C. et al. Membranization of coacervates into artificial phagocytes with predation toward bacteria. ACS Nano 15, 10048–10057 (2021).

    CAS  PubMed  Google Scholar 

  22. Gao, S. & Srivastava, S. Comb polyelectrolytes stabilize complex coacervate microdroplet dispersions. ACS Macro Lett. 11, 902–909 (2022).

    CAS  PubMed  Google Scholar 

  23. Li, Q. et al. A self-templated route to monodisperse complex droplets as artificial extremophile-mimic from coacervate-liposome interplay. Preprint at bioRxiv https://doi.org/10.1101/2021.02.19.432011 (2022).

  24. Yin, C., Lin, Z., Jiang, X., Martin, N. & Tian, L. Engineering the coacervate microdroplet interface via polyelectrolyte and surfactant complexation. ACS Appl. Mater. Interfaces 15, 27447–27456 (2023).

    CAS  PubMed  Google Scholar 

  25. Ji, Y., Lin, Y. & Qiao, Y. Plant cell-inspired membranization of coacervate protocells with a structured polysaccharide layer. J. Am. Chem. Soc. 145, 12576–12585 (2023).

    CAS  PubMed  Google Scholar 

  26. Cuylen, S. et al. Ki-67 acts as a biological surfactant to disperse mitotic chromosomes. Nature 535, 308–312 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Simon, J. R., Carroll, N. J., Rubinstein, M., Chilkoti, A. & López, G. P. Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity. Nat. Chem. 9, 509–515 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Folkmann, A. W., Putnam, A., Lee, C. F. & Seydoux, G. Regulation of biomolecular condensates by interfacial protein clusters. Science 373, 1218–1224 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kelley, F. M., Favetta, B., Regy, R. M., Mittal, J. & Schuster, B. S. Amphiphilic proteins coassemble into multiphasic condensates and act as biomolecular surfactants. Proc. Natl Acad. Sci. USA 118, e2109967118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Tschurikow, X. et al. Amphiphiles formed from synthetic DNA-nanomotifs mimic the stepwise dispersal of transcriptional clusters in the cell nucleus. Nano Lett. 23, 7815–7824 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Thody, S. A. et al. Small-molecule properties define partitioning into biomolecular condensates. Nat. Chem. 16, 1794–1802 (2024).

    Google Scholar 

  32. Panganiban, B. et al. Random heteropolymers preserve protein function in foreign environments. Science 359, 1239–1243 (2018).

    CAS  PubMed  Google Scholar 

  33. Ruan, Z. et al. Population-based heteropolymer design to mimic protein mixtures. Nature 615, 251–258 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu, C. et al. A boronic acid-rich dendrimer with robust and unprecedented efficiency for cytosolic protein delivery and CRISPR-Cas9 gene editing. Sci. Adv. 5, eaaw8922 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Santos, F. K. G., Neto, E. L. B., Moura, M. C. P., Dantas, T. N. C. & Neto, A. A. D. Molecular behavior of ionic and nonionic surfactants in saline medium. Colloids Surf. A 333, 156–162 (2009).

    CAS  Google Scholar 

  36. Taylor, N. O., Wei, M. T., Stone, H. A. & Brangwynne, C. P. Quantifying dynamics in phase-separated condensates using fluorescence recovery after photobleaching. Biophys. J. 117, 1285–1300 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Yewdall, N. A. et al. Physicochemical characterization of polymer-stabilized coacervate protocells. ChemBioChem 20, 2643–2652 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Lu, T. & Spruijt, E. Multiphase complex coacervate droplets. J. Am. Chem. Soc. 142, 2905–2914 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Rana, U. et al. Asymmetric oligomerization state and sequence patterning can tune multiphase condensate miscibility. Nat. Chem. 16, 1073–1082 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Huang, Y. et al. Encoding coacervate droplets with paramagnetism for dynamical reconfigurability and spatial addressability. ACS Nano 17, 6234–6246 (2023).

    CAS  PubMed  Google Scholar 

  41. Kota, D., Prasad, R. & Zhou, H. X. Adenosine triphosphate mediates phase separation of disordered basic proteins by bridging intermolecular interaction networks. J. Am. Chem. Soc. 146, 1326–1336 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Eid, J., Greige-Gerges, H., Monticelli, L. & Jraij, A. Elastic moduli of lipid membranes: reproducibility of AFM measures. Chem. Phys. Lipids 234, 105011 (2021).

    CAS  PubMed  Google Scholar 

  43. Riback, J. A. et al. Stress-triggered phase separation is an adaptive, evolutionarily tuned response. Cell 168, 1028–1040 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Yu, M. & Nishiumi, H. Theory of phase separation in mixtures with lower critical solution temperature. J. Phys. Chem. 96, 842–845 (1992).

    CAS  Google Scholar 

  45. Davis, C. R., Martinez, C. J., Howarter, J. A. & Erk, K. A. Diffusion-controlled spontaneous emulsification of water-soluble oils via micelle swelling. Langmuir 36, 7517–7527 (2020).

    CAS  PubMed  Google Scholar 

  46. Sacanna, S., Kegel, W. K. & Philipse, A. P. Thermodynamically stable Pickering emulsions. Phys. Rev. Lett. 98, 158301 (2007).

    CAS  PubMed  Google Scholar 

  47. Oron, A., Davis, S. H. & Bankoff, S. G. Long-scale evolution of thin liquid films. Mod. Phys. 69, 931 (1997).

    CAS  Google Scholar 

  48. Lee, J. & Babadagli, T. Comprehensive review on heavy-oil emulsions: colloid science and practical applications. Chem. Eng. Sci. 228, 115962 (2020).

    CAS  Google Scholar 

  49. Bates, F. S. & Fredrickson, G. H. Block copolymers—designer soft materials. Phys. Today 52, 32–38 (1999).

    CAS  Google Scholar 

  50. Heggestad, J. T., Fontes, C. M., Joh, D. Y., Hucknall, A. M. & Chilkoti, A. In pursuit of zero 2.0: recent developments in nonfouling polymer brushes for immunoassays. Adv. Mater. 32, e1903285 (2020).

    PubMed  Google Scholar 

  51. Shen, J., Liu, G., Han, Y. & Jin, W. Artificial channels for confined mass transport at the sub-nanometre scale. Nat. Rev. Mater. 6, 294–312 (2021).

    CAS  Google Scholar 

  52. Sitarska, E. et al. Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles. Nat. Commun. 14, 5644 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Estirado, E. M., Mason, A. F., Garcia, M. Á. A., van Hest, J. C. M. & Brunsveld, L. Supramolecular nanoscaffolds within cytomimetic protocells as signal localization hubs. J. Am. Chem. Soc. 142, 9106–9111 (2020).

    Google Scholar 

  54. Liu, S. et al. Enzyme-mediated nitric oxide production in vasoactive erythrocyte membrane-enclosed coacervate protocells. Nat. Chem. 12, 1165–1173 (2020).

    CAS  PubMed  Google Scholar 

  55. Priftis, D. & Tirrell, M. Phase behaviour and complex coacervation of aqueous polypeptide solutions. Soft Matter 8, 9396–9405 (2012).

    CAS  Google Scholar 

  56. Baruch Leshem, A. et al. Biomolecular condensates formed by designer minimalistic peptides. Nat. Commun. 14, 421 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Bohidar, H., Dubin, P. L., Majhi, P. R., Tribet, C. & Jaeger, W. Effects of protein-polyelectrolyte affinity and polyelectrolyte molecular weight on dynamic properties of bovine serum albumin-poly(diallyldimethylammonium chloride) coacervates. Biomacromolecules 6, 1573–1585 (2005).

    CAS  PubMed  Google Scholar 

  58. Chen, N., Zhao, Z., Wang, Y. & Dimova, R. Resolving the mechanisms of soy glycinin self-coacervation and hollow-condensate formation. ACS Macro Lett. 9, 1844–1852 (2020).

    CAS  PubMed  Google Scholar 

  59. Schuster, B. S. et al. Controllable protein phase separation and modular recruitment to form responsive membraneless organelles. Nat. Commun. 9, 2985 (2018).

    PubMed  PubMed Central  Google Scholar 

  60. Mohanty, P. et al. A synergy between site-specific and transient interactions drives the phase separation of a disordered, low-complexity domain. Proc. Natl Acad. Sci. USA 120, e2305625120 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Patel, A. et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066–1077 (2015).

    CAS  PubMed  Google Scholar 

  62. Huang, Y. et al. Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology. Nat. Commun. 14, 5444 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Mitrea, D. M. et al. Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA. eLife 5, e13571 (2016).

    PubMed  PubMed Central  Google Scholar 

  64. Ye, S. et al. Micropolarity governs the structural organization of biomolecular condensates. Nat. Chem. Biol. 20, 443–451 (2024).

    CAS  PubMed  Google Scholar 

  65. Volpe, C. D. & Siboni, S. The Wilhelmy method: a critical and practical review. Surf. Innov. 6, 120–132 (2018).

    Google Scholar 

  66. Ijavi, M. et al. Surface tensiometry of phase separated protein and polymer droplets by the sessile drop method. Soft Matter 17, 1655–1662 (2021).

    CAS  PubMed  Google Scholar 

  67. Frey, S. et al. Surface properties determining passage rates of proteins through nuclear pores. Cell 174, 202–217.e9 (2018).

    CAS  PubMed  Google Scholar 

  68. Yang, T. et al. Droplet-based microfluidic temperature-jump platform for the rapid assessment of biomolecular kinetics. Anal. Chem. 94, 16675–16684 (2022).

    CAS  PubMed  Google Scholar 

  69. Villois, A. et al. Droplet microfluidics for the label-free extraction of complete phase diagrams and kinetics of liquid–liquid phase separation in finite volumes. Small 18, 2202606 (2022).

    CAS  Google Scholar 

  70. Beneyton, T., Love, C., Girault, M., Tang, T. Y. D. & Baret, J. C. High-throughput synthesis and screening of functional coacervates using microfluidics. ChemSystemsChem 2, e2000022 (2020).

    CAS  Google Scholar 

  71. Wang, W. et al. Highly robust crystalsome via directed polymer crystallization at curved liquid/liquid interface. Nat. Commun. 7, 10599 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Tang, D. et al. Universal membranization of synthetic coacervates and biomolecular condensates towards ultrastability and spontaneous emulsification. figshare https://doi.org/10.6084/m9.figshare.28069118 (2024).

Download references

Acknowledgements

L.J. is in debt to X. Zhang from Westlake University and X. Yang from South China University of Technology for their advice on protein condensates. L.J. acknowledges support by the National Natural Science Foundation of China (numbers 22122201 and 22272060), the CYGJ Program of Guangzhou (number 2024D03J0003), the State Key Laboratory of Pulp and Paper Engineering (numbers 2024QN09, 2024ZD01 and 2024ZD06), the TCL Science and Technology Innovation Fund (number x2fkE5240020), the Guangdong Basic and Applied Basic Research Foundation (number 2023A1515010956), the Fundamental Research Funds for the Central Universities (number 2024ZYGXZR017) and the Recruitment Program of Guangdong (number 2016ZT06C322).

Author information

Authors and Affiliations

  1. South China Advanced Institute for Soft Matter Science and Technology (AISMST), State Key Laboratory of Pulp and Paper Engineering, School of Emergent Soft Matter, South China University of Technology, Guangzhou, China

    Da Tang, Jun Zhu, Hao Wang, Hui Wang & Lingxiang Jiang

  2. Guangdong Provincial Key Laboratory of Functional and Intelligent Hybrid Materials and Devices, Guangdong Basic Research Center of Excellence for Energy and Information Polymer Materials, South China University of Technology, Guangzhou, China

    Da Tang, Jun Zhu, Hao Wang, Hui Wang & Lingxiang Jiang

  3. Department of Nutrition and Food Hygiene, School of Public Health, Guangzhou Medical University, Guangzhou, China

    Nannan Chen

  4. Cooperative Innovation Center of Industrial Fermentation (Ministry of Education and Hubei Province), Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China

    Yongqi Huang

Authors
  1. Da Tang
    View author publications

    Search author on:PubMed Google Scholar

  2. Jun Zhu
    View author publications

    Search author on:PubMed Google Scholar

  3. Hao Wang
    View author publications

    Search author on:PubMed Google Scholar

  4. Nannan Chen
    View author publications

    Search author on:PubMed Google Scholar

  5. Hui Wang
    View author publications

    Search author on:PubMed Google Scholar

  6. Yongqi Huang
    View author publications

    Search author on:PubMed Google Scholar

  7. Lingxiang Jiang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

D.T. and L.J. conceived the project and designed the experiments. D.T. performed most of the experiments. J.Z. expressed and purified the proteins. Hao Wang conducted the FLIM experiments to measure the micropolarity and viscosity of condensed phases. N.C. provided the SG protein. Hui Wang suggested the monomer selection for protein affinity. Y.H. advised on the preparation of protein condensates. All the authors analysed the data and contributed to discussing the results and writing the paper.

Corresponding author

Correspondence to Lingxiang Jiang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Additional methods, Supplementary Tables 1–7, Figs. 1–28 and Notes 1–4.

Supplementary Video 1

Brownian motion and anti-fusing dynamics of CAP-laden droplets (COND1@CAP15) in cell-sized confinement.

Supplementary Video 2

Collision events of closely packed membranized droplets (COND3@CAP15) do not lead to fusion.

Supplementary Video 3

Optical tweezers manipulate the collision and fusion of membraneless droplets (COND3).

Supplementary Video 4

Optical tweezers force the collision and deformation of the membranized droplets (COND3@CAP23).

Supplementary Video 5

Spontaneous emulsification observed by transmission channel (COND1@CAP15).

Supplementary Video 6

Spontaneous emulsification by fluorescence channel (COND1@CAP15).

Source Data for Supplementary Figures

Source data for Supplementary figures (this file is also uploaded to figshare 10.6084/m9.figshare.28069118).

Source data

Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

Source Data Fig. 5

Statistical source data.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tang, D., Zhu, J., Wang, H. et al. Universal membranization of synthetic coacervates and biomolecular condensates towards ultrastability and spontaneous emulsification. Nat. Chem. 17, 911–923 (2025). https://doi.org/10.1038/s41557-025-01800-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41557-025-01800-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing