- Open Access
Active transport as a mechanism of microphase selection in biomolecular condensates
Phys. Rev. Research 8, 033345 – Published 21 September, 2026
DOI: https://doi.org/10.1103/wk2j-3bz9
Abstract
The size and organization of biomolecular condensates formed by liquid-liquid phase separation are set by multiple cellular mechanisms that are not yet fully understood. Here, we identify a transport-driven mechanism: Stochastic binding of phase-separating proteins to cytoskeletal motor proteins, followed by active redistribution along filament networks, generates an effective long-range repulsion that arrests coarsening and selects a finite condensate size. A minimal diffusion-transport model, analyzed by linear stability theory and three-dimensional simulations, reveals a transition from macroscopic to microphase separation at remarkably low binding/release fractions, corresponding to minute motor-bound populations. Tuning motor binding rates or transport velocities enables sublinear control of condensate sizes () from a few hundred nanometers up to the micron scale. The selected length scale is robust to the intrinsic shot noise of the binding-release reactions. In anisotropic cytoskeletal environments, transport asymmetry drives morphological transitions from spherical to cylindrical condensates, independently of the thermodynamic parameters. This mechanism provides a versatile, spatiotemporally programmable route to condensate organization and informs the design of synthetic active emulsions with tunable architectures.
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References (71)
- C. P. Brangwynne, C. R. Eckmann, D. S. Courson, A. Rybarska, C. Hoege, J. Gharakhani, F. Jülicher, and A. A. Hyman, Germline P granules are liquid droplets that localize by controlled dissolution/condensation, Science 324, 1729 (2009).
- S. Alberti, A. Gladfelter, and T. Mittag, Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates, Cell 176, 419 (2019).
- C. P. Brangwynne, Phase transitions and size scaling of membrane-less organelles, J. Cell Biol. 203, 875 (2013).
- S. Alberti and A. A. Hyman, Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing, Nat. Rev. Mol. Cell Biol. 22, 196 (2021).
- A. A. Hyman, C. A. Weber, and F. Jülicher, Liquid-liquid phase separation in biology, Annu. Rev. Cell Dev. Biol. 30, 39 (2014).
- E. Stroo, M. Koopman, E. A. A. Nollen, and A. Mata-Cabana, Cellular regulation of amyloid formation in aging and disease, Front. Neurosci. 11, 64 (2017).
- M. Linsenmeier, L. Faltova, C. Morelli, U. Capasso Palmiero, C. Seiffert, A. M. Küffner, D. Pinotsi, J. Zhou, R. Mezzenga, and P. Arosio, The interface of condensates of the hnRNPA1 low-complexity domain promotes formation of amyloid fibrils, Nat. Chem. 15, 1340 (2023).
- Y. Shin and C. P. Brangwynne, Liquid phase condensation in cell physiology and disease, Science 357, eaaf4382 (2017).
- G. Vecchi, P. Sormanni, B. Mannini, A. Vandelli, G. G. Tartaglia, C. M. Dobson, F. U. Hartl, and M. Vendruscolo, Proteome-wide observation of the phenomenon of life on the edge of solubility, Proc. Natl. Acad. Sci. USA 117, 1015 (2020).
- R. Alert, P. Tierno, and J. Casademunt, Formation of metastable phases by spinodal decomposition, Nat. Commun. 7, 13067 (2016).
- A. J. Bray, Theory of phase-ordering kinetics, Adv. Phys. 51, 481 (2002).
- C. A. Weber, D. Zwicker, F. Jülicher, and C. F. Lee, Physics of active emulsions, Rep. Prog. Phys. 82, 064601 (2019).
- S. C. Glotzer, E. A. Di Marzio, and M. Muthukumar, Chemically controlled pattern formation in phase-separating materials, Il Nuovo Cimento D 16, 1171 (1994).
- S. C. Glotzer, E. A. Di Marzio, and M. Muthukumar, Reaction-controlled morphology of phase-separating mixtures, Phys. Rev. Lett. 74, 2034 (1995).
- J. J. Christensen, K. Elder, and H. C. Fogedby, Phase segregation dynamics of a chemically reactive binary mixture, Phys. Rev. E 54, R2212(R) (1996).
- D. Carati and R. Lefever, Chemical freezing of phase separation in immiscible binary mixtures, Phys. Rev. E 56, 3127 (1997).
- D. Zwicker, A. A. Hyman, and F. Jülicher, Suppression of Ostwald ripening in active emulsions, Phys. Rev. E 92, 012317 (2015).
- J. D. Wurtz and C. F. Lee, Chemical-reaction-controlled phase separated drops: Formation, size selection, and coarsening, Phys. Rev. Lett. 120, 078102 (2018).
- M. Hondele, R. Sachdev, S. Heinrich, J. Wang, P. Vallotton, B. M. A. Fontoura, and K. Weis, DEAD-box ATPases are global regulators of phase-separated organelles, Nature (London) 573, 144 (2019).
- J. Kirschbaum and D. Zwicker, Controlling biomolecular condensates via chemical reactions, J. R. Soc. Interface 18, 20210255 (2021).
- H. H. Schede, P. Natarajan, A. K. Chakraborty, and K. Shrinivas, A model for organization and regulation of nuclear condensates by gene activity, Nat. Commun. 14, 4152 (2023).
- N. Ziethen, J. Kirschbaum, and D. Zwicker, Nucleation of chemically active droplets, Phys. Rev. Lett. 130, 248201 (2023).
- G. Häfner and M. Müller, Reaction-driven assembly: Controlling changes in membrane topology by reaction cycles, Soft Matter 19, 7281 (2023).
- E. Zippo, D. Dormann, T. Speck, and L. S. Stelzl, Molecular simulations of enzymatic phosphorylation of disordered proteins and their condensates, Nat. Commun. 16, 4649 (2025).
- T. S. Harmon and F. Jülicher, Molecular assembly lines in active droplets, Phys. Rev. Lett. 128, 108102 (2022).
- F. Brauns, H. Weyer, J. Halatek, J. Yoon, and E. Frey, Wavelength selection by interrupted coarsening in reaction-diffusion systems, Phys. Rev. Lett. 126, 104101 (2021).
- V. S. Doan, I. Alshareedah, A. Singh, P. R. Banerjee, and S. Shin, Diffusiophoresis promotes phase separation and transport of biomolecular condensates, Nat. Commun. 15, 7686 (2024).
- J. D. Fries, R. Berthin, C. Luo, M. Jardat, D. Zwicker, V. Dahirel, and P. Illien, Chemically active droplets in crowded environments, Phys. Rev. E 112, 064410 (2025).
- R. Rossetto, G. Wellecke, and D. Zwicker, Binding and dimerization control phase separation in a compartment, Phys. Rev. Res. 7, 023145 (2025).
- T. Litschel, C. F. Kelley, X. Cheng, L. Babl, N. Mizuno, L. B. Case, and P. Schwille, Membrane-induced 2D phase separation of the focal adhesion protein talin, Nat. Commun. 15, 4986 (2024).
- C. Luo, N. Hess, D. Aierken, Y. Qiang, J. A. Joseph, and D. Zwicker, Theory of condensate size control by molecular charge asymmetry, ACS Macro Lett. 14, 1484 (2025).
- A. W. Folkmann, A. Putnam, C. F. Lee, and G. Seydoux, Regulation of biomolecular condensates by interfacial protein clusters, Science 373, 1218 (2021).
- X. Wei, J. Zhou, Y. Wang, and F. Meng, Modeling elastically mediated liquid-liquid phase separation, Phys. Rev. Lett. 125, 268001 (2020).
- J. X. Liu, M. P. Haataja, A. Košmrlj, S. S. Datta, C. B. Arnold, and R. D. Priestley, Liquid–liquid phase separation within fibrillar networks, Nat. Commun. 14, 6085 (2023).
- R. W. Style, T. Sai, N. Fanelli, M. Ijavi, K. Smith-Mannschott, Q. Xu, L. A. Wilen, and E. R. Dufresne, Liquid-liquid phase separation in an elastic network, Phys. Rev. X 8, 011028 (2018).
- T. Yokoyama, Y. Qiang, D. Zwicker, and A. Nikoubashman, Molecular simulations of phase separation in elastic polymer networks, J. Phys. Chem. B 130, 4885 (2026).
- Q. Bodini–Lefranc, J. Schindelwig, D. Weidinger, L. Engleder, and S. Fürthauer, Arrested coarsening, oscillations, and memory from a conserved phase separating nucleator in a self-straining cytoskeletal network, arXiv:2509.07181.
- M. A. Kiebler and K. E. Bauer, RNA granules in flux: Dynamics to balance physiology and pathology, Nat. Rev. Neurosci. 25, 711 (2024).
- C. Appert-Rolland, M. Ebbinghaus, and L. Santen, Intracellular transport driven by cytoskeletal motors: General mechanisms and defects, Phys. Rep. 593, 1 (2015).
- N. P. Tsai, Y. C. Tsui, and L. N. Wei, Dynein motor contributes to stress granule dynamics in primary neurons, Neuroscience 159, 647 (2009).
- M. Loschi, C. C. Leishman, N. Berardone, and G. L. Boccaccio, Dynein and kinesin regulate stress-granule and P-body dynamics, J. Cell Sci. 122, 3973 (2009).
- A. Cochard, A. Safieddine, P. Combe, M.-N. Benassy, D. Weil, and Z. Gueroui, Condensate functionalization with microtubule motors directs their nucleation in space and allows manipulating RNA localization, EMBO J. 42, EMBJ2023114106 (2023).
- L. Foret, A simple mechanism of raft formation in two-component fluid membranes, Europhys. Lett. 71, 508 (2005).
- H. Garcke, J. Kampmann, A. Rätz, and M. R. Röger, A coupled surface-Cahn-Hilliard bulk-diffusion system modeling lipid raft formation in cell membranes, Math. Models Methods Appl. Sci. 26, 1149 (2016).
- F. Schmid, Physical mechanisms of micro- and nanodomain formation in multicomponent lipid membranes, Biochim. Biophys. Acta. Biomembr. 1859, 509 (2017).
- D. T. Gillespie, The chemical Langevin equation, J. Chem. Phys. 113, 297 (2000).
- M. J. I. Müller, S. Klumpp, and R. Lipowsky, Bidirectional transport by molecular motors: Enhanced processivity and response to external forces, Biophys. J. 98, 2610 (2010).
- K. Joshi, H. M. York, C. S. Wright, R. R. Biswas, S. Arumugam, and S. Iyer-Biswas, Emergent spatiotemporal organization in stochastic intracellular transport dynamics, Annu. Rev. Biophys. 53, 193 (2024).
- A. Caspi, R. Granek, and M. Elbaum, Enhanced diffusion in active intracellular transport, Phys. Rev. Lett. 85, 5655 (2000).
- C. P. Brangwynne, G. H. Koenderink, F. C. MacKintosh, and D. A. Weitz, Intracellular transport by active diffusion, Trends Cell Biol. 19, 423 (2009).
- G. H. Fredrickson, Analytical solution of a model of integrin-cytoskeletal interactions in migrating fibroblasts, J. Phys. II France 5, 369 (1995).
- W. Paul and J. Baschnagel, Stochastic Processes, 2nd ed. (Springer, Berlin, Heidelberg, 2013).
- Y. I. Li and M. E. Cates, Non-equilibrium phase separation with reactions: A canonical model and its behaviour, J. Stat. Mech. (2020) 053206.
- T. Ohta and A. Ito, Dynamics of phase separation in copolymer-homopolymer mixtures, Phys. Rev. E 52, 5250 (1995).
- S. A. Brazovskii, Phase transitions of an isotropic system to a nonuniform state, Zh. Eksp. Teor. Fiz. 68, 175 (1975) [Sov. Phys. JETP 41, 85 (1975)].
- See Supplemental Material at http://link.aps.org/supplemental/10.1103/wk2j-3bz9 for movies of droplet evolution at and for quench depth with and without noise ( and 0.5).
- B. Vorselaars, R. K. W. Spencer, and M. W. Matsen, Instability of the microemulsion channel in block copolymer-homopolymer blends, Phys. Rev. Lett. 125, 117801 (2020).
- T. Ohta and K. Kawasaki, Equilibrium morphology of block copolymer melts, Macromolecules 19, 2621 (1986).
- J. P. Gillies, S. R. Little, A. Siva, W. O. Hancock, and M. E. DeSantis, Cargo adaptor identity controls the mechanism and kinetics of dynein activation, J. Biol. Chem. 301, 108358 (2025).
- J. J. Hummel and C. C. Hoogenraad, Specific KIF1A–adaptor interactions control selective cargo recognition, J. Cell Biol. 220, e202105011 (2021).
- A. J. Firestone, J. S. Weinger, M. Maldonado, K. Barlan, L. D. Langston, M. O'Donnell, V. I. Gelfand, T. M. Kapoor, and J. K. Chen, Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein, Nature (London) 484, 125 (2012).
- E. A. Kumar, D. S. Tsao, and M. R. Diehl, Motor mutants bring wild-type motors to a halt stochastically, Biophys. J. 107, 279 (2014).
- M. Batish, P. van den Bogaard, F. R. Kramer, and S. Tyagi, Neuronal mRNAs travel singly into dendrites, Proc. Natl. Acad. Sci. USA 109, 4645 (2012).
- Q. Geng, J. J. Keya, T. Hotta, and K. J. Verhey, The kinesin-3 KIF1C undergoes liquid-liquid phase separation for accumulation of specific transcripts at the cell periphery, EMBO J. 43, 3192 (2024).
- Y. Dai, L. You, and A. Chilkoti, Engineering synthetic biomolecular condensates, Nat. Rev. Bioeng. 1, 466 (2023).
- A. T. Lombardo, S. R. Nelson, G. G. Kennedy, K. M. Trybus, S. Walcott, and D. M. Warshaw, Myosin Va transport of liposomes in three-dimensional actin networks is modulated by actin filament density, position, and polarity, Proc. Natl. Acad. Sci. USA 116, 8326 (2019).
- S. E. Cason and E. L. F. Holzbaur, Selective motor activation in organelle transport along axons, Nat. Rev. Mol. Cell Biol. 23, 699 (2022).
- J. Laprade, L. B. Frechette, C. Amey, A. T. Cusi, A. Baskaran, W. B. Rogers, and G. Duclos, The coarsening of biomimetic condensates in an active fluid is non-self-similar, Nat. Phys. 22, 612 (2026).
- J. Berry, C. P. Brangwynne, and M. Haataja, Physical principles of intracellular organization via active and passive phase transitions, Rep. Prog. Phys. 81, 046601 (2018).
- L. Qiao, P. Gispert, L. S. Stelzl, and F. Schmid, Dataset: Active transport as a mechanism of microphase selection in biomolecular condensates (Version 1.0) [Dataset], Zenodo, 2026, doi: 10.5281/zenodo.21780549.
- L. Qiao, N. Ilow, M. Ignacio, and G. W. Slater, An empirical method to characterize displacement distribution functions for anomalous and transient diffusion, Physica A 604, 127676 (2022).