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.

  • Focus Review
  • Published:

A minimalist design approach to simple coacervates from low-molecular-weight components

Polymer Journal volume 57, pages 815–829 (2025)Cite this article

Subjects

Abstract

Coacervates are condensed, liquid-like assemblies formed through liquid–liquid phase separation via associative interactions among molecular components. Owing to their membraneless nature, coacervates exhibit unique dynamic features, such as coalescence and molecular sequestration, thus serving as promising platforms for drug delivery and the regulation of biological events. In this Focus Review, representative examples of simple coacervates composed of phase-separating low-molecular-weight molecules (LMWMs) are highlighted. This review provides a minimalist design strategy for LMWM-based simple coacervates based on surfactants and peptides and summarizes their unique functions, including stimulus-responsive structural transformations. The sophisticated design of these droplets is expected to enable a wide range of applications, including studies on the origins of life, the development of artificial cells, intracellular and in vivo protein delivery, biosensing, and molecular computing.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Aumiller WM Jr, Keating CD. Experimental models for dynamic compartmentalization of biomolecules in liquid organelles: Reversible formation and partitioning in aqueous biphasic systems. Adv Colloid Interface Sci. 2017;239:75–87.

    Article  CAS  PubMed  Google Scholar 

  2. Abbas M, Lipiński WP, Wang J, Spruijt E. Peptide-based coacervates as biomimetic protocells. Chem Soc Rev. 2021;50:3690–705.

    Article  CAS  PubMed  Google Scholar 

  3. Cook AB, Novosedlik S, van Hest JCM. Complex coacervate materials as artificial cells. Acc Mater Res. 2023;4:287–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. de Jong HGB, Kruyt HR. Coacervation (partial miscibility in colloid systems). Proc K Ned Akad Wet. 1929;32:849–56.

    Google Scholar 

  6. Oparin AI. The origin of life and the origin of enzymes. Adv Enzymol Relat Areas Mol Biol. 1965;27:347–80.

    Article  PubMed  Google Scholar 

  7. Strulson CA, Molden RC, Keating CD, Bevilacqua PC. RNA catalysis through compartmentalization. Nat Chem. 2012;4:941–6.

    Article  CAS  PubMed  Google Scholar 

  8. Dora Tang T-Y, Rohaida Che Hak C, Thompson AJ, Kuimova MK, Williams DS, Perriman AW, et al. Fatty acid membrane assembly on coacervate microdroplets as a step towards a hybrid protocell model. Nat Chem. 2014;6:527–33.

    Article  CAS  PubMed  Google Scholar 

  9. Qiao Y, Li M, Booth R, Mann S. Predatory behaviour in synthetic protocell communities. Nat Chem. 2017;9:110–9.

    Article  CAS  PubMed  Google Scholar 

  10. Drobot B, Iglesias-Artola JM, Le Vay K, Mayr V, Kar M, Kreysing M, et al. Compartmentalised RNA catalysis in membrane-free coacervate protocells. Nat Commun. 2018;9:3643.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Martin N, Douliez J-P, Qiao Y, Booth R, Li M, Mann S. Antagonistic chemical coupling in self-reconfigurable host-guest protocells. Nat Commun. 2018;9:3652.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Poudyal RR, Guth-Metzler RM, Veenis AJ, Frankel EA, Keating CD, Bevilacqua PC. Template-directed RNA polymerization and enhanced ribozyme catalysis inside membraneless compartments formed by coacervates. Nat Commun. 2019;10:490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mason AF, Yewdall NA, Welzen PLW, Shao J, van Stevendaal M, van Hest JCM, et al. Mimicking cellular compartmentalization in a hierarchical protocell through spontaneous spatial organization. ACS Cent Sci. 2019;5:1360–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Altenburg WJ, Yewdall NA, Vervoort DFM, van Stevendaal MHME, Mason AF, van Hest JCM. Programmed spatial organization of biomacromolecules into discrete, coacervate-based protocells. Nat Commun. 2020;11:6282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu J, Tian L, Qiao Y, Zhou S, Patil AJ, Wang K, et al. Hydrogel-immobilized coacervate droplets as modular microreactor assemblies. Angew Chem Int Ed. 2020;59:6853–9.

    Article  CAS  Google Scholar 

  16. Gobbo P, Tian L, Pavan Kumar BVVS, Turvey S, Cattelan M, Patil AJ, et al. Catalytic processing in ruthenium-based polyoxometalate coacervate protocells. Nat Commun. 2020;11:41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shin Y, Brangwynne CP. Liquid phase condensation in cell physiology and disease. Science. 2017;357:eaaf4382.

    Article  PubMed  Google Scholar 

  18. Banani SF, Lee HO, Hyman AA, Rosen MK. Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol. 2017;18:285–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Alberti S, Hyman AA. Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing. Nat Rev Mol Cell Biol. 2021;22:196–213.

    Article  CAS  PubMed  Google Scholar 

  20. Lafontaine DLJ, Riback JA, Bascetin R, Brangwynne CP. The nucleolus as a multiphase liquid condensate. Nat Rev Mol Cell Biol. 2021;22:165–82.

    Article  CAS  PubMed  Google Scholar 

  21. Frenkel-Pinter M, Samanta M, Ashkenasy G, Leman LJ. Prebiotic peptides: molecular hubs in the origin of life. Chem Rev. 2020;120:4707–65.

    Article  CAS  PubMed  Google Scholar 

  22. Koga S, Williams DS, Perriman AW, Mann S. Peptide-nucleotide microdroplets as a step towards a membrane-free protocell model. Nat Chem. 2011;3:720–4.

    Article  CAS  PubMed  Google Scholar 

  23. Mason AF, Buddingh’ BC, Williams DS, van Hest JCM. Hierarchical self-assembly of a copolymer-stabilized coacervate protocell. J Am Chem Soc. 2017;139:17309–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Douliez J-P, Martin N, Gaillard C, Beneyton T, Baret J-C, Mann S, et al. Catanionic coacervate droplets as a surfactant-based membrane-free protocell model. Angew Chem Int Ed. 2017;56:13689–93.

    Article  CAS  Google Scholar 

  25. Tian L, Li M, Patil AJ, Drinkwater BW, Mann S. Artificial morphogen-mediated differentiation in synthetic protocells. Nat Commun. 2019;10:3321.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Donau C, Späth F, Sosson M, Kriebisch BAK, Schnitter F, Tena-Solsona M, et al. Active coacervate droplets as a model for membraneless organelles and protocells. Nat Commun. 2020;11:5167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bhattacharya A, Niederholtmeyer H, Podolsky KA, Bhattacharya R, Song J-J, Brea RJ, et al. Lipid sponge droplets as programmable synthetic organelles. Proc Natl Acad Sci Usa. 2020;117:18206–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Matsuo M, Kurihara K. Proliferating coacervate droplets as the missing link between chemistry and biology in the origins of life. Nat Commun. 2021;12:5487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ianeselli A, Tetiker D, Stein J, Kühnlein A, Mast CB, Braun D, et al. Non-equilibrium conditions inside rock pores drive fission, maintenance and selection of coacervate protocells. Nat Chem. 2022;14:32–39.

    Article  CAS  PubMed  Google Scholar 

  30. Akishiba M, Takeuchi T, Kawaguchi Y, Sakamoto K, Yu H-H, Nakase I, et al. Cytosolic antibody delivery by lipid-sensitive endosomolytic peptide. Nat Chem. 2017;9:751–61.

    Article  CAS  PubMed  Google Scholar 

  31. Liu S, Zhang Y, Li M, Xiong L, Zhang Z, Yang X, et al. Enzyme-mediated nitric oxide production in vasoactive erythrocyte membrane-enclosed coacervate protocells. Nat Chem. 2020;12:1165–73.

    Article  CAS  PubMed  Google Scholar 

  32. Iwata T, Hirose H, Sakamoto K, Hirai Y, Arafiles JVV, Akishiba M, et al. Liquid droplet formation and facile cytosolic translocation of IgG in the presence of attenuated cationic amphiphilic lytic peptides. Angew Chem Int Ed. 2021;60:19804–12.

    Article  CAS  Google Scholar 

  33. Bracha D, Walls MT, Brangwynne CP. Probing and engineering liquid-phase organelles. Nat Biotechnol. 2019;37:1435–45.

    Article  CAS  PubMed  Google Scholar 

  34. Shin Y, Berry J, Pannucci N, Haataja MP, Toettcher JE, Brangwynne CP. Spatiotemporal control of intracellular phase transitions using light-activated optoDroplets. Cell. 2017;168:159–71.e14.

    Article  CAS  PubMed  Google Scholar 

  35. Nakamura H, Lee AA, Afshar AS, Watanabe S, Rho E, Razavi S, et al. Intracellular production of hydrogels and synthetic RNA granules by multivalent molecular interactions. Nat Mater. 2018;17:79–89.

    Article  CAS  PubMed  Google Scholar 

  36. Dine E, Gil AA, Uribe G, Brangwynne CP, Toettcher JE. Protein phase separation provides long-term memory of transient spatial stimuli. Cell Syst. 2018;6:655–63.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Reinkemeier CD, Girona GE, Lemke EA. Designer membraneless organelles enable codon reassignment of selected mRNAs in eukaryotes. Science 2019;363:eaaw2644.

  38. Kim NY, Lee S, Yu J, Kim N, Won SS, Park H, et al. Optogenetic control of mRNA localization and translation in live cells. Nat Cell Biol. 2020;22:341–52.

    Article  CAS  PubMed  Google Scholar 

  39. Garabedian MV, Wang W, Dabdoub JB, Tong M, Caldwell RM, Benman W, et al. Designer membraneless organelles sequester native factors for control of cell behavior. Nat Chem Biol. 2021;17:998–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yoshikawa M, Yoshii T, Ikuta M, Tsukiji S. Synthetic protein condensates that inducibly recruit and release protein activity in living cells. J Am Chem Soc. 2021;143:6434–46.

    Article  CAS  PubMed  Google Scholar 

  41. Helfrich MR, Mangeney-Slavin LK, Long MS, Djoko KY, Keating CD. Aqueous phase separation in giant vesicles. J Am Chem Soc. 2002;124:13374–5.

    Article  CAS  PubMed  Google Scholar 

  42. Long MS, Jones CD, Helfrich MR, Mangeney-Slavin LK, Keating CD. Dynamic microcompartmentation in synthetic cells. Proc Natl Acad Sci Usa. 2005;102:5920–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Obayashi H, Wakabayashi R, Kamiya N, Goto M. Supramolecular localization in liquid-liquid phase separation and protein recruitment in confined droplets. Chem Commun. 2023;59:414–7.

    Article  CAS  Google Scholar 

  44. Quiroz FG, Chilkoti A. Sequence heuristics to encode phase behaviour in intrinsically disordered protein polymers. Nat Mater. 2015;14:1164–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wei W, Petrone L, Tan Y, Cai H, Israelachvili JN, Miserez A, et al. An underwater surface-drying peptide inspired by a mussel adhesive protein. Adv Funct Mater. 2016;26:3496–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jia TZ, Chandru K, Hongo Y, Afrin R, Usui T, Myojo K, et al. Membraneless polyester microdroplets as primordial compartments at the origins of life. Proc Natl Acad Sci Usa. 2019;116:15830–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gabryelczyk B, Cai H, Shi X, Sun Y, Swinkels PJM, Salentinig S, et al. Hydrogen bond guidance and aromatic stacking drive liquid-liquid phase separation of intrinsically disordered histidine-rich peptides. Nat Commun. 2019;10:5465.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kuroyanagi S, Shimada N, Fujii S, Furuta T, Harada A, Sakurai K, et al. Highly ordered polypeptide with UCST phase separation behavior. J Am Chem Soc. 2019;141:1261–8.

    Article  CAS  PubMed  Google Scholar 

  49. Dzuricky M, Rogers BA, Shahid A, Cremer PS, Chilkoti A. De novo engineering of intracellular condensates using artificial disordered proteins. Nat Chem. 2020;12:814–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Scott WA, Gharakhanian EG, Bell AG, Evans D, Barun E, Houk KN, et al. Active controlled and tunable coacervation using side-chain functional α-helical homopolypeptides. J Am Chem Soc. 2021;143:18196–203.

    Article  CAS  PubMed  Google Scholar 

  51. Sun Y, Lau SY, Lim ZW, Chang SC, Ghadessy F, Partridge A, et al. Phase-separating peptides for direct cytosolic delivery and redox-activated release of macromolecular therapeutics. Nat Chem. 2022;14:274–83.

    Article  CAS  PubMed  Google Scholar 

  52. Niu J, Qiu C, Abbott NL, Gellman SH. Formation of versus recruitment to RNA-rich condensates: controlling effects exerted by peptide side chain identity. J Am Chem Soc. 2022;144:10386–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Deepankumar K, Guo Q, Mohanram H, Lim J, Mu Y, Pervushin K, et al. Liquid-liquid phase separation of the green mussel adhesive protein Pvfp-5 is regulated by the post-translated dopa amino acid. Adv Mater. 2022;34:e2103828.

    Article  PubMed  Google Scholar 

  54. Sun Y, Wu X, Li J, Radiom M, Mezzenga R, Verma CS, et al. Phase-separating peptide coacervates with programmable material properties for universal intracellular delivery of macromolecules. Nat Commun. 2024;15:10094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Fares HM, Marras AE, Ting JM, Tirrell MV, Keating CD. Impact of wet-dry cycling on the phase behavior and compartmentalization properties of complex coacervates. Nat Commun. 2020;11:5423.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wibowo A, Osada K, Matsuda H, Anraku Y, Hirose H, Kishimura A, et al. Morphology control in water of polyion complex nanoarchitectures of double-hydrophilic charged block copolymers through composition tuning and thermal treatment. Macromolecules. 2014;47:3086–92.

    Article  CAS  Google Scholar 

  57. Sing CE, Perry SL. Recent progress in the science of complex coacervation. Soft Matter. 2020;16:2885–914.

    Article  CAS  PubMed  Google Scholar 

  58. Kaur T, Raju M, Alshareedah I, Davis RB, Potoyan DA, Banerjee PR. Sequence-encoded and composition-dependent protein-RNA interactions control multiphasic condensate morphologies. Nat Commun. 2021;12:872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tsuruta M, Torii T, Kohata K, Kawauchi K, Tateishi-Karimata H, Sugimoto N, et al. Controlling liquid-liquid phase separation of G-quadruplex-forming RNAs in a sequence-specific manner. Chem Commun. 2022;58:12931–4.

    Article  CAS  Google Scholar 

  60. Wollny D, Vernot B, Wang J, Hondele M, Safrastyan A, Aron F, et al. Characterization of RNA content in individual phase-separated coacervate microdroplets. Nat Commun. 2022;13:2626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Simon JR, Carroll NJ, Rubinstein M, Chilkoti A, López GP. Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity. Nat Chem. 2017;9:509–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Deshpande S, Brandenburg F, Lau A, Last MGF, Spoelstra WK, Reese L, et al. Spatiotemporal control of coacervate formation within liposomes. Nat Commun. 2019;10:1800.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Linsenmeier M, Kopp MRG, Grigolato F, Emmanoulidis L, Liu D, Zürcher D, et al. Dynamics of synthetic membraneless organelles in microfluidic droplets. Angew Chem Int Ed. 2019;58:14489–94.

    Article  CAS  Google Scholar 

  64. Sato Y, Sakamoto T, Takinoue M. Sequence-based engineering of dynamic functions of micrometer-sized DNA droplets. Sci Adv. 2020;6:eaba3471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mountain GA, Keating CD. Formation of multiphase complex coacervates and partitioning of biomolecules within them. Biomacromolecules. 2020;21:630–40.

    Article  CAS  PubMed  Google Scholar 

  66. Lu T, Spruijt E. Multiphase complex coacervate droplets. J Am Chem Soc. 2020;142:2905–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fisher RS, Elbaum-Garfinkle S. Tunable multiphase dynamics of arginine and lysine liquid condensates. Nat Commun. 2020;11:4628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chen Y, Yuan M, Zhang Y, Liu S, Yang X, Wang K, et al. Construction of coacervate-in-coacervate multi-compartment protocells for spatial organization of enzymatic reactions. Chem Sci. 2020;11:8617–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mu W, Ji Z, Zhou M, Wu J, Lin Y, Qiao Y. Membrane-confined liquid-liquid phase separation toward artificial organelles. Sci Adv. 2021;7:eabf9000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Karoui H, Seck MJ, Martin N. Self-programmed enzyme phase separation and multiphase coacervate droplet organization. Chem Sci. 2021;12:2794–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lu T, Liese S, Schoenmakers L, Weber CA, Suzuki H, Huck WTS, et al. Endocytosis of coacervates into liposomes. J Am Chem Soc. 2022;144:13451–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gong J, Tsumura N, Sato Y, Takinoue M. Computational DNA droplets recognizing miRNA sequence inputs based on liquid–liquid phase separation. Adv Funct Mater. 2022;32:2202322.

    Article  CAS  Google Scholar 

  73. Gao N, Xu C, Yin Z, Li M, Mann S. Triggerable protocell capture in nanoparticle-caged coacervate microdroplets. J Am Chem Soc. 2022;144:3855–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Donau C, Späth F, Stasi M, Bergmann AM, Boekhoven J. Phase transitions in chemically fueled, multiphase complex coacervate droplets. Angew Chem Int Ed. 2022:61;e202211905.

  75. Iglesias-Artola JM, Drobot B, Kar M, Fritsch AW, Mutschler H, Dora Tang T-Y, et al. Charge-density reduction promotes ribozyme activity in RNA-peptide coacervates via RNA fluidization and magnesium partitioning. Nat Chem. 2022;14:407–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Choi S, Meyer MO, Bevilacqua PC, Keating CD. Phase-specific RNA accumulation and duplex thermodynamics in multiphase coacervate models for membraneless organelles. Nat Chem. 2022;14:1110–7.

    Article  CAS  PubMed  Google Scholar 

  77. Jain A, Kassem S, Fisher RS, Wang B, Li T-D, Wang T, et al. Connected peptide modules enable controlled co-existence of self-assembled fibers inside liquid condensates. J Am Chem Soc. 2022;144:15002–7.

    Article  CAS  PubMed  Google Scholar 

  78. Xu C, Martin N, Li M, Mann S. Living material assembly of bacteriogenic protocells. Nature. 2022;609:1029–37.

    Article  CAS  PubMed  Google Scholar 

  79. Erkamp NA, Sneideris T, Ausserwöger H, Qian D, Qamar S, Nixon-Abell J, et al. Spatially non-uniform condensates emerge from dynamically arrested phase separation. Nat Commun. 2023;14:684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Oana H, Kishimura A, Yonehara K, Yamasaki Y, Washizu M, Kataoka K. Spontaneous formation of giant unilamellar vesicles from microdroplets of a polyion complex by thermally induced phase separation. Angew Chem Int Ed. 2009;48:4613–6.

    Article  CAS  Google Scholar 

  81. Higashiguchi K, Taira G, Kitai J-I, Hirose T, Matsuda K. Photoinduced macroscopic morphological transformation of an amphiphilic diarylethene assembly: reversible dynamic motion. J Am Chem Soc. 2015;137:2722–9.

    Article  CAS  PubMed  Google Scholar 

  82. Aumiller WM Jr, Keating CD. Phosphorylation-mediated RNA/peptide complex coacervation as a model for intracellular liquid organelles. Nat Chem. 2016;8:129–37.

    Article  CAS  PubMed  Google Scholar 

  83. Garenne D, Beven L, Navailles L, Nallet F, Dufourc EJ, Douliez J-P. Sequestration of proteins by fatty acid coacervates for their encapsulation within vesicles. Angew Chem Int Ed. 2016;55:13475–9.

    Article  CAS  Google Scholar 

  84. Nakashima KK, Baaij JF, Spruijt E. Reversible generation of coacervate droplets in an enzymatic network. Soft Matter. 2018;14:361–7.

    Article  CAS  PubMed  Google Scholar 

  85. Nishida K, Tamura A, Yui N. pH-Responsive coacervate droplets formed from acid-labile methylated polyrotaxanes as an injectable protein carrier. Biomacromolecules. 2018;19:2238–47.

    Article  CAS  PubMed  Google Scholar 

  86. Ianiro A, Wu H, van Rijt MMJ, Vena MP, Keizer ADA, Esteves ACC, et al. Liquid-liquid phase separation during amphiphilic self-assembly. Nat Chem. 2019;11:320–8.

    Article  CAS  PubMed  Google Scholar 

  87. Jang Y, Hsieh M-C, Dautel D, Guo S, Grover MA, Champion JA. Understanding the coacervate-to-vesicle transition of globular fusion proteins to engineer protein vesicle size and membrane heterogeneity. Biomacromolecules. 2019;20:3494–503.

    Article  CAS  PubMed  Google Scholar 

  88. Love C, Steinkühler J, Gonzales DT, Yandrapalli N, Robinson T, Dimova R, et al. Reversible pH-responsive coacervate formation in lipid vesicles activates dormant enzymatic reactions. Angew Chem Int Ed. 2020;59:5950–7.

    Article  CAS  Google Scholar 

  89. Alshareedah I, Moosa MM, Raju M, Potoyan DA, Banerjee PR. Phase transition of RNA−protein complexes into ordered hollow condensates. Proc Natl Acad Sci USA. 2020;117:15650–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Nakashima KK, van Haren MHI, André AAM, Robu I, Spruijt E. Active coacervate droplets are protocells that grow and resist Ostwald ripening. Nat Commun. 2021;12:3819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Abbas M, Lipiński WP, Nakashima KK, Huck WTS, Spruijt E. A short peptide synthon for liquid-liquid phase separation. Nat Chem. 2021;13:1046–54.

    Article  CAS  PubMed  Google Scholar 

  92. Späth F, Donau C, Bergmann AM, Kränzlein M, Synatschke CV, Rieger B, et al. Molecular design of chemically fueled peptide-polyelectrolyte coacervate-based assemblies. J Am Chem Soc. 2021;143:4782–9.

    Article  PubMed  Google Scholar 

  93. Dautel DR, Champion JA. Protein vesicles self-assembled from functional globular proteins with different charge and size. Biomacromolecules. 2021;22:116–25.

    Article  CAS  PubMed  Google Scholar 

  94. Bergmann AM, Donau C, Späth F, Jahnke K, Göpfrich K, Boekhoven J. Evolution and single-droplet analysis of fuel-driven compartments by droplet-based microfluidics. Angew Chem Int Ed. 2022;61:e202203928.

    Article  CAS  Google Scholar 

  95. Du X, Zhou J, Shi J, Xu B. Supramolecular hydrogelators and hydrogels: from soft matter to molecular biomaterials. Chem Rev. 2015;115:13165–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Panja S, Adams DJ. Stimuli responsive dynamic transformations in supramolecular gels. Chem Soc Rev. 2021;50:5165–5200.

    Article  CAS  PubMed  Google Scholar 

  97. Kubota R, Hamachi I. Cell-like synthetic supramolecular soft materials realized in multicomponent, non-/out-of-equilibrium dynamic systems. Adv Sci. 2023;11:e2306830.

  98. Kubota R. Supramolecular–polymer composite hydrogels: from in situ network observation to functional properties. Bull Chem Soc Jpn. 2023;96:802–12.

    Article  CAS  Google Scholar 

  99. Cohen I, Hiskey CF, Oster G. Critical phenomena in aqueous solutions of long-chain quaternary ammonium salts. J Colloid Sci. 1954;9:243–53.

    Article  CAS  Google Scholar 

  100. Cohen I, Vassiliades T. Critical phenomena in aqueous solutions of long chain quaternary ammonium salts. II. Specificity and light scattering properties. J Phys Chem. 1961;65:1774–81.

    Article  CAS  Google Scholar 

  101. Jho Y, Yoo HY, Lin Y, Han S, Hwang DS. Molecular and structural basis of low interfacial energy of complex coacervates in water. Adv Colloid Interface Sci. 2017;239:61–73.

    Article  CAS  PubMed  Google Scholar 

  102. Strey R, Jahn W, Porte G, Bassereau P. Freeze fracture electron microscopy of dilute lamellar and anomalous isotropic (L3) phases. Langmuir. 1990;6:1635–9.

    Article  CAS  Google Scholar 

  103. Hoffmann H, Thunig C, Munkert U, Meyer HW, Richter W. From vesicles to the L3 (sponge) phase in alkyldimethylamine oxide/heptanol systems. Langmuir. 1992;8:2629–38.

    Article  CAS  Google Scholar 

  104. Wydro MJ, Warr GG, Atkin R. Amplitude-modulated atomic force microscopy reveals the near surface nanostructure of surfactant sponge (L3) and lamellar (Lα) phases. Langmuir. 2015;31:5513–20.

    Article  CAS  PubMed  Google Scholar 

  105. Kim S, Huang J, Lee Y, Dutta S, Yoo HY, Jung YM, et al. Complexation and coacervation of like-charged polyelectrolytes inspired by mussels. Proc Natl Acad Sci USA. 2016;113:E847–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Huang K-Y, Yoo HY, Jho Y, Han S, Hwang DS. Bicontinuous fluid structure with low cohesive energy: molecular basis for exceptionally low interfacial tension of complex coacervate fluids. ACS Nano. 2016;10:5051–62.

    Article  CAS  PubMed  Google Scholar 

  107. Manoj Lalwani S, Eneh CI, Lutkenhaus JL. Emerging trends in the dynamics of polyelectrolyte complexes. Phys Chem Chem Phys. 2020;22:24157–77.

    Article  CAS  PubMed  Google Scholar 

  108. Peresypkin AV, Menger FM. Zwitterionic geminis. coacervate formation from a single organic compound. Org Lett. 1999;1:1347–50.

    Article  CAS  Google Scholar 

  109. Menger FM, Peresypkin AV, Caran KL, Apkarian RP. A sponge morphology in an elementary coacervate. Langmuir. 2000;16:9113–6.

    Article  CAS  Google Scholar 

  110. Menger FM, Peresypkin AV. A combinatorially-derived structural phase diagram for 42 zwitterionic geminis. J Am Chem Soc. 2001;123:5614–5.

    Article  CAS  PubMed  Google Scholar 

  111. Imura T, Yanagishita H, Kitamoto D. Coacervate formation from natural glycolipid: one acetyl group on the headgroup triggers coacervate-to-vesicle transition. J Am Chem Soc. 2004;126:10804–5.

    Article  CAS  PubMed  Google Scholar 

  112. Yotsuji H, Higashiguchi K, Sato R, Shigeta Y, Matsuda K. Phototransformative supramolecular assembly of amphiphilic diarylethenes realized by a combination of photochromism and lower critical solution temperature behavior. Chem Eur J. 2017;23:15059–66.

    Article  CAS  PubMed  Google Scholar 

  113. Nojima T, Iyoda T. Water-rich fluid material containing orderly condensed proteins. Angew Chem Int Ed. 2017;56:1308–12.

    Article  CAS  Google Scholar 

  114. Nojima T, Iyoda T. Egg white-based strong hydrogel via ordered protein condensation. NPG Asia Mater. 2018;10:e460.

    Article  Google Scholar 

  115. Shigemitsu H, Hamachi I. Design strategies of stimuli-responsive supramolecular hydrogels relying on structural analyses and cell-mimicking approaches. Acc Chem Res. 2017;50:740–50.

    Article  CAS  PubMed  Google Scholar 

  116. Sheehan F, Sementa D, Jain A, Kumar M, Tayarani-Najjaran M, Kroiss D, et al. Peptide-based supramolecular systems chemistry. Chem Rev. 2021;121:13869–914.

    Article  CAS  PubMed  Google Scholar 

  117. Reches M, Gazit E. Casting metal nanowires within discrete self-assembled peptide nanotubes. Science. 2003;300:625–7.

    Article  CAS  PubMed  Google Scholar 

  118. Yang Z, Liang G, Wang L, Xu B. Using a kinase/phosphatase switch to regulate a supramolecular hydrogel and forming the supramolecular hydrogel in vivo. J Am Chem Soc. 2006;128:3038–43.

    Article  CAS  PubMed  Google Scholar 

  119. Ikeda M, Tanida T, Yoshii T, Hamachi I. Rational molecular design of stimulus-responsive supramolecular hydrogels based on dipeptides. Adv Mater. 2011;23:2819–22.

    Article  CAS  PubMed  Google Scholar 

  120. Ikeda M, Tanida T, Yoshii T, Kurotani K, Onogi S, Urayama K, et al. Installing logic-gate responses to a variety of biological substances in supramolecular hydrogel-enzyme hybrids. Nat Chem. 2014;6:511–8.

    Article  CAS  PubMed  Google Scholar 

  121. Onogi S, Shigemitsu H, Yoshii T, Tanida T, Ikeda M, Kubota R, et al. In situ real-time imaging of self-sorted supramolecular nanofibres. Nat Chem. 2016;8:743–52.

    Article  CAS  PubMed  Google Scholar 

  122. Yuan C, Levin A, Chen W, Xing R, Zou Q, Herling TW, et al. Nucleation and growth of amino acid and peptide supramolecular polymers through liquid-liquid phase separation. Angew Chem Int Ed. 2019;58:18116–23.

    Article  CAS  Google Scholar 

  123. Shen Y, Ruggeri FS, Vigolo D, Kamada A, Qamar S, Levin A, et al. Biomolecular condensates undergo a generic shear-mediated liquid-to-solid transition. Nat Nanotechnol. 2020;15:841–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Tang Y, Bera S, Yao Y, Zeng J, Lao Z, Dong X, et al. Prediction and characterization of liquid-liquid phase separation of minimalistic peptides. Cell Rep. Phys Sci. 2021;2:100579.

    Article  CAS  Google Scholar 

  125. Joseph JA, Reinhardt A, Aguirre A, Chew PY, Russell KO, Espinosa JR, et al. Physics-driven coarse-grained model for biomolecular phase separation with near-quantitative accuracy. Nat Comput Sci. 2021;1:732–43.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Adachi K, Kawaguchi K. Predicting heteropolymer interactions: demixing and hypermixing of disordered protein sequences. Phys Rev X. 2024;14:031011.

  127. Murthy AC, Dignon GL, Kan Y, Zerze GH, Parekh SH, Mittal J, et al. Molecular interactions underlying liquid-liquid phase separation of the FUS low-complexity domain. Nat Struct Mol Biol. 2019;26:637–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Martin EW, Holehouse AS, Peran I, Farag M, Incicco JJ, Bremer A, et al. Valence and patterning of aromatic residues determine the phase behavior of prion-like domains. Science. 2020;367:694–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Abbas M, Law JO, Grellscheid SN, Huck WTS, Spruijt E. Peptide-based coacervate-core vesicles with semipermeable membranes. Adv. Mater. 2022;34:e2202913.

  130. Bao Y, Chen H, Xu Z, Gao J, Jiang L, Xia J. Photo-responsive phase-separating fluorescent molecules for intracellular protein delivery. Angew Chem Int Ed. 2023;62:e202307045.

    Article  CAS  Google Scholar 

  131. Bao Y, Xu Z, Cheng K, Li X, Chen F, Yuan D, et al. Staudinger reaction-responsive coacervates for cytosolic antibody delivery and TRIM21-mediated protein degradation. J Am Chem Soc. 2025;147:3830–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ado G, Noda N, Vu HT, Perron A, Mahapatra AD, Arista KP, et al. Discovery of a phase-separating small molecule that selectively sequesters tubulin in cells. Chem Sci. 2022;13:5760–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kubota R, Torigoe S, Hamachi I. Temporal stimulus patterns drive differentiation of a synthetic dipeptide-based coacervate. J Am Chem Soc. 2022;144:15155–64.

    Article  CAS  PubMed  Google Scholar 

  134. Zhang H, Elbaum-Garfinkle S, Langdon EM, Taylor N, Occhipinti P, Bridges AA, et al. RNA controls polyQ protein phase transitions. Mol Cell. 2015;60:220–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Folkmann AW, Putnam A, Lee CF, Seydoux G. Regulation of biomolecular condensates by interfacial protein clusters. Science. 2021;373:1218–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Blocher M, Liu D, Luisi PL. Liposome-assisted selective polycondensation of α-amino acids and peptides: the case of charged liposomes. Macromolecules. 2000;33:5787–96.

    Article  CAS  Google Scholar 

  137. Izgu EC, Björkbom A, Kamat NP, Lelyveld VS, Zhang W, Jia TZ, et al. N-Carboxyanhydride-mediated fatty acylation of amino acids and peptides for functionalization of protocell membranes. J Am Chem Soc. 2016;138:16669–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kholodenko BN, Hancock JF, Kolch W. Signalling ballet in space and time. Nat Rev Mol Cell Biol. 2010;11:414–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Purvis JE, Lahav G. Encoding and decoding cellular information through signaling dynamics. Cell. 2013;152:945–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Cai L, Dalal CK, Elowitz MB. Frequency-modulated nuclear localization bursts coordinate gene regulation. Nature. 2008;455:485–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ashall L, Horton CA, Nelson DE, Paszek P, Harper CV, Sillitoe K, et al. Pulsatile stimulation determines timing and specificity of NF-κB-dependent transcription. Science. 2009;324:242–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Imayoshi I, Isomura A, Harima Y, Kawaguchi K, Kori H, Miyachi H, et al. Oscillatory control of factors determining multipotency and fate in mouse neural progenitors. Science. 2013;342:1203–8.

    Article  CAS  PubMed  Google Scholar 

  143. Teders M, Pogodaev AA, Bojanov G, Huck WTS. Reversible photoswitchable inhibitors generate ultrasensitivity in out-of-equilibrium enzymatic reactions. J Am Chem Soc. 2021;143:5709–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Kubota R, Hiroi T, Ikuta Y, Liu Y, Hamachi I. Visualizing formation and dynamics of a three-dimensional sponge-like network of a coacervate in real time. J Am Chem Soc. 2023;145:18316–28.

    Article  CAS  PubMed  Google Scholar 

  145. Feric M, Vaidya N, Harmon TS, Mitrea DM, Zhu L, Richardson TM, et al. Coexisting liquid phases underlie nucleolar subcompartments. Cell. 2016;165:1686–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Jain S, Wheeler JR, Walters RW, Agrawal A, Barsic A, Parker R. ATPase-modulated stress granules contain a diverse proteome and substructure. Cell. 2016;164:487–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the JST FOREST Program (Grant Number JPMJFR2328, Japan) and by a Grant-in-Aid for Scientific Research (B) (JSPS KAKENHI Grant JP22H02195, Japan).

Author information

Authors and Affiliations

  1. Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Moto-oka, Nishi-ku, Fukuoka, 819-0395, Japan

    Ryou Kubota

Authors
  1. Ryou Kubota
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Ryou Kubota.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

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

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

Kubota, R. A minimalist design approach to simple coacervates from low-molecular-weight components. Polym J 57, 815–829 (2025). https://doi.org/10.1038/s41428-025-01037-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41428-025-01037-5

Search

Advanced search

Quick links