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A framework for understanding the functions of biomolecular condensates across scales
Open accessAbstract
Biomolecular condensates are found throughout eukaryotic cells, including in the nucleus, in the cytoplasm and on membranes. They are also implicated in a wide range of cellular functions, organizing molecules that act in processes ranging from RNA metabolism to signalling to gene regulation. Early work in the field focused on identifying condensates and understanding how their physical properties and regulation arise from molecular constituents. Recent years have brought a focus on understanding condensate functions. Studies have revealed functions that span different length scales: from molecular (modulating the rates of chemical reactions) to mesoscale (organizing large structures within cells) to cellular (facilitating localization of cellular materials and homeostatic responses). In this Roadmap, we discuss representative examples of biochemical and cellular functions of biomolecular condensates from the recent literature and organize these functions into a series of non-exclusive classes across the different length scales. We conclude with a discussion of areas of current interest and challenges in the field, and thoughts about how progress may be made to further our understanding of the widespread roles of condensates in cell biology.
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“The second systems biology criterion follows from the observation that integrated function is only possible via structured spatial heterogeneity, that is, that spatial heterogeneity is crucial to cellular function.”
From ‘Whole Organism’, Systems Biology, and Top-Down Criteria for Evaluating Scenarios for the Origin of Life (2021) · cites this paper as [45]
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Site-specific ubiquitylation acts as a regulator of linker histone H1
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PARP1 condensates differentially partition DNA repair proteins and enhance DNA ligation
Sang, C. C., Moore, G., Tereshchenko, M., Zhang, H., Nosella, M. L., Dasovich, M., Alderson, T. R., Leung, A. K. L., Finkelstein, I. J., Forman-Kay, J. D., et al. (2024) · EMBO Reports · doi:10.1038/s44319-024-00285-5 · Cited by 40
“…biogenesis (Lafontaine et al, 2021; Correll et al, 2019), stress responses (Lau et al, 2020; Hofmann et al, 2021), and signal transduction (Su et al, 2021; Case et al, 2019) by concentrating speci fi c components and in fl uencing biochemical reaction rates (Banani et al, 2017; Lyon et al, 2021).”
Cavitation controls droplet sizes in elastic media
Vidal-Henriquez, E., & Zwicker, D. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2102014118 · Cited by 40
“We expect similar behaviors for biomolecular condensates, which often form as a response to changes in temperature, pH, salt concentration, or protein concentration in cells [30, 31, 32, 33].”
BackgroundIntegrated Cryo-Correlative Microscopy for Targeted Structural Investigation In Situ
Smeets, M., Bieber, A., Capitanio, C., Schiøtz, O. H., van der Heijden, T., Effting, A. P. J., Piel, É., Lazem, B., Erdmann, P. S., & Plitzko, J. M. (2021) · Microscopy Today · doi:10.1017/s1551929521001280 · Cited by 40
Chromatin Liquid–Liquid Phase Separation (LLPS) Is Regulated by Ionic Conditions and Fiber Length
Chen, Q., Zhao, L., Soman, A., Arkhipova, A. Y., Li, J., Li, H., Chen, Y., Shi, X., & Nordenskiöld, L. (2022) · Cells · doi:10.3390/cells11193145 · Cited by 40
Li, M., Park, B. M., Dai, X., Xu, Y., Huang, J., & Sun, F. (2022) · Nature Communications · doi:10.1038/s41467-022-30933-0 · Cited by 38
Theory and Simulation of Multiphase Coexistence in Biomolecular Mixtures
Jacobs, W. M. (2023) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.3c00198 · Cited by 40
“For broader context, we encourage the reader to consult other recent works, including reviews that emphasize the biological functionality and regulation of condensates [15, 46], the interplay between physical gelation and phase separation of multivalent macromolecules [47], and the conformational dynamics of macromole…”
BackgroundDisrupting pathologic phase transitions in neurodegeneration
Hurtle, B. T., Xie, L., & Donnelly, C. J. (2023) · Journal of Clinical Investigation · doi:10.1172/jci168549 · Cited by 40
“By spatiotemporally organizing biomolecules, unique biomolecular condensates dictate the biosynthesis, transport, regulation, and function of the basic building blocks necessary for cellular homeostasis (28, 30, 32, 36, 89, 90).”
BackgroundSupramolecular Switching of Liquid‐Liquid Phase Separation for Orchestrating Enzyme Kinetics
Wang, D., Zhou, L., Zhang, X.-K., Zhou, Z., Huang, Z., & Gao, N. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202422601 · Cited by 39
Zerze, G. H. (2023) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.2c01273 · Cited by 36
Barrat, J., Gado, E. D., Egelhaaf, S. U., Mao, X., Dijkstra, M., Pine, D. J., Kumar, S. K., Bishop, K. J. M., Gang, O., Obermeyer, A. C., et al. (2023) · Journal of Physics Materials · doi:10.1088/2515-7639/ad06cc · Cited by 51
A functional map of the human intrinsically disordered proteome
Pritišanac, I., Alderson, T. R., Kolarić, Đ., Zarin, T., Xie, S., Lu, A. X., Alam, A., Maqsood, A., Youn, J., Forman-Kay, J. D., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2604562123 · Cited by 38
Cell-cycle-dependent mRNA localization in P-bodies
Safieddine, A., Benassy, M., Bonte, T., Slimani, F., Pourcelot, O., Kress, M., Ernoult‐Lange, M., Courel, M., Coleno, E., Imbert, A., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.09.011 · Cited by 38
Smad4 sequestered in SFPQ condensates prevents TGF-β tumor-suppressive signaling
Xiao, M., Wang, F., Chen, N., Zhang, H., Cao, J., Yu, Y., Zhao, B., Ji, J., Xu, P., Li, L., et al. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.11.020 · Cited by 39
Functional specificity in biomolecular condensates revealed by genetic complementation
Sabari, B. R., Hyman, A. A., & Hnisz, D. (2024) · Nature Reviews Genetics · doi:10.1038/s41576-024-00780-4 · Cited by 35
“Hypotheses of the biological functions that could emerge from condensates include increasing the reaction speed, stopping reactions and buffering biochemical noise 4,5,10,11 .”
Liu, S., Wang, C., Latham, A. P., Ding, X., & Zhang, B. (2023) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1011442 · Cited by 33
Bobáľová, J., Strouhalová, D., & Bobáľ, P. (2023) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c00886 · Cited by 36
Mohanty, P., Rizuan, A., Kim, Y. C., Fawzi, N. L., & Mittal, J. (2023) · Protein Science · doi:10.1002/pro.4891 · Cited by 35
“The assembly and internal architecture of these condensates is dependent on the network of inter-molecular interactions formed between multivalent, multidomain proteins and nucleic acids (Lyon et al., 2021; Sanders et al., 2020).”
BackgroundHydrogen-Bonded Network of Water in Phase-Separated Biomolecular Condensates
Joshi, A., Avni, A., Walimbe, A., Rai, S. K., Sarkar, S., & Mukhopadhyay, S. (2024) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.4c01153 · Cited by 36
Biomolecular condensates as stress sensors and modulators of bacterial signaling
Sasazawa, M., Tomares, D. T., Childers, W. S., & Saurabh, S. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1012413 · Cited by 36
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Sequence-dependent conformational transitions of disordered proteins during condensation
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Conformational Properties of Polymers at Droplet Interfaces as Model Systems for Disordered Proteins
Wang, J., Devarajan, D. S., Nikoubashman, A., & Mittal, J. (2023) · ACS Macro Letters · doi:10.1021/acsmacrolett.3c00456 · Cited by 32
Physics of droplet regulation in biological cells
Zwicker, D., Paulin, O. W., & ter Burg, C. (2025) · Reports on Progress in Physics · doi:10.1088/1361-6633/ae12a7 · Cited by 43
Subcellular localization as a driver of protein function
Sigaeva, A., Hutchings, C., Cesnik, A. J., Lilley, K. S., & Lundberg, E. K. (2026) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-026-00947-3 · Cited by 39
“The dynamic formation and dissolution of these phase separated condensates facilitates many spatiotemporally defined processes 52,120 .”
Neuronal biomolecular condensates and their implications in neurodegenerative diseases
Nam, J., & Gwon, Y. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1145420 · Cited by 34
“De-mixed with the surrounding phase, biomolecular condensates embrace a subset of molecules of related functions, promoting many biological processes in themselves (Lyon et al., 2021).”
BackgroundThe two action mechanisms of plant cryptochromes
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Metadata
- Authors
- Lyon, A. S., Peeples, W. B., & Rosen, M. K.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Rosen, Michael K.
- Venue
- Nature Reviews Molecular Cell Biology
- Published
- 2020-11-09
- Volume
- 22
- Issue
- 3
- Pages
- 215-235
- ISSN
- 1471-0072 (ISSN-L)
- 1471-0080
- PMC
- PMC8574987
- OpenAlex
- W3099323319
- Cited by
- 895
- References
- 233
- Citations by year
- 2026: 149 · 2025: 186 · 2024: 175 · 2023: 172 · 2022: 115 · 2021: 95 · 2020: 2
- FWCI
- 9.35
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Reviews Molecular Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (F32GM136058)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- biomolecular condensates, liquid-liquid phase separation, length scales, RNA metabolism, gene expression regulation, cell organization, signal transduction, reaction rate, cellular homeostasis
- MeSH terms
- Animals, Biochemical Phenomena, Cell Physiological Phenomena, Cytoplasm, Eukaryotic Cells, Humans, Organelles, Macromolecular Substances, Multiprotein Complexes, Protein Aggregates
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