- Physical Review Journals
All JournalsPhysics Magazine

Physical Review Research

Reuse & Permissions

It is not necessary to obtain permission to reuse this article or its components as it is available under the terms of the Creative Commons Attribution 4.0 International license. This license permits unrestricted use, distribution, and reproduction in any medium, provided attribution to the author(s) and the published article's title, journal citation, and DOI are maintained. Please note that some figures may have been included with permission from other third parties. It is your responsibility to obtain the proper permission from the rights holder directly for these figures.

Export citation

Export citation

Choose format for download:

Download Citation
  • Open Access

Formation of extracellular vesicles depends on mechanical feedback of the cortex and the glycocalyx

Ke Xiao1 and Padmini Rangamani1,2,*

  • *Contact author: prangamani@health.ucsd.edu
PDF

Phys. Rev. Research 8, 013012 – Published 8 January, 2026

DOI: https://doi.org/10.1103/543w-yg1m

Abstract

Cell-secreted extracellular vesicles (EVs) play a pivotal role in local and distant cell-to-cell communication by delivering specific cargoes to other cells or to the extracellular space. In many cells, the glycocalyx, a thick sugar-rich layer at the cell surface, and the membrane-cortex attachment are crucially linked to the formation of EVs. However, it remains unclear as to what determines the successful formation of EVs when multiple physical factors are involved. In this work, we developed a model for glycocalyx-membrane-cortex composite to investigate the effects of glycocalyx and membrane-cortex adhesion on the formation of EVs by combining polymer physics-based theory and Helfrich membrane theory. By performing linear stability analysis, we show that modulating the mechanical feedback among the glycocalyx, membrane-cortex attachment, and membrane curvature can give rise to two types of instabilities: a conserved Turing-type instability and a Cahn-Hilliard-type instability. Furthermore, using an equilibrium model, we identified two critical conditions for EV formation: an initial detachment of the membrane from the underlying cortex and then a sufficient driving force to induce membrane deformation for successful EV formation. We further demonstrated that there exists an optimal glycocalyx coating area at which the formation of EVs is most favorable. Finally, we use our model to predict that a heterogeneous size distribution of EVs can be generated through the regulation of glycocalyx properties, shedding insight into how EVs of different radii may be generated.

View figure in article

Physics Subject Headings (PhySH)

Article Text

References (147)

  1. D. K. Jeppesen, Q. Zhang, J. L. Franklin, and R. J. Coffey, Extracellular vesicles and nanoparticles: Emerging complexities, Trends Cell Biol. 33, 667 (2023).
  2. D. K. Jeppesen, A. M. Fenix, J. L. Franklin, J. N. Higginbotham, Q. Zhang, L. J. Zimmerman, D. C. Liebler, J. Ping, Q. Liu, R. Evans, W. H. Fissell, J. G. Patton, L. H. Rome, D. T. Burnette, and R. J. Coffey, Reassessment of exosome composition, Cell 177, 428 (2019).
  3. M. A. Kumar, S. K. Baba, H. Q. Sadida, S. A. Marzooqi, J. Jerobin, F. H. Altemani, N. Algehainy, M. A. Alanazi, A.-B. Abou-Samra, R. Kumar, A. S. Al-Shabeeb Akil, M. A. Macha, R. Mir, and A. A. Bhat, Extracellular vesicles as tools and targets in therapy for diseases, Sig. Transduct. Target. Ther. 9, 27 (2024).
  4. J. A. Welsh, et al., Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches, J. Extracell. Vesicles 13, e12404 (2024).
  5. M. Sheta, E. A. Taha, Y. Lu, and T. Eguchi, Extracellular vesicles: New classification and tumor immunosuppression, Biology 12, 110 (2023).
  6. T. Ahmadzada, S. Kao, G. Reid, S. Clarke, G. E. Grau, and E. Hosseini-Beheshti, Extracellular vesicles as biomarkers in malignant pleural mesothelioma: A review, Crit. Rev. Oncol. Hematol. 150, 102949 (2020).
  7. A. Becker, B. K. Thakur, J. M. Weiss, H. S. Kim, H. Peinado, and D. Lyden, Extracellular vesicles in cancer: Cell-to-cell mediators of metastasis, Cancer Cell 30, 836 (2016).
  8. L. A. Hargett and N. N. Bauer, On the origin of microparticles: From “platelet dust” to mediators of intercellular communication, Pulm. Circ. 3, 329 (2013).
  9. K. Segawa, J. Suzuki, and S. Nagata, Constitutive exposure of phosphatidylserine on viable cells, Proc. Natl. Acad. Sci. USA 108, 19246 (2011).
  10. J. D. Arroyo, J. R. Chevillet, E. M. Kroh, I. K. Ruf, C. C. Pritchard, D. F. Gibson, P. S. Mitchell, C. F. Bennett, E. L. Pogosova-Agadjanyan, D. L. Stirewalt, J. F. Tait, and M. Tewari, Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma, Proc. Natl. Acad. Sci. USA 108, 5003 (2011).
  11. K. C. Vickers, B. T. Palmisano, B. M. Shoucri, R. D. Shamburek, and A. T. Remaley, MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins, Nat. Cell Biol. 13, 423 (2011).
  12. H. Zhao, A. Achreja, E. Iessi, M. Logozzi, D. Mizzoni, R. Di Raimo, D. Nagrath, and S. Fais, The key role of extracellular vesicles in the metastatic process, Biochim. Biophys. Acta Rev. Cancer 1869, 64 (2018).
  13. D. E. Reynolds, P. Vallapureddy, R.-T. T. Morales, D. Oh, M. Pan, U. Chintapula, R. L. Linardi, A. M. Gaesser, K. Ortved, and J. Ko, Equine mesenchymal stem cell derived extracellular vesicle immunopathology biomarker discovery, J. Ex. Bio. 2, e89 (2023).
  14. S. Muraoka, A. M. DeLeo, M. K. Sethi, K. Yukawa-Takamatsu, Z. Yang, J. Ko, J. D. Hogan, Z. Ruan, Y. You, Y. Wang, M. Medalla, S. Ikezu, M. Chen, W. Xia, S. Gorantla, H. E. Gendelman, D. Issadore, J. Zaia, and T. Ikezu, Proteomic and biological profiling of extracellular vesicles from Alzheimer's disease human brain tissues, Alzheimer's Dement. 16, 896 (2020).
  15. C. Jiang, F. Hopfner, D. Berg, M. T. Hu, A. Pilotto, B. Borroni, J. J. Davis, and G. K. Tofaris, Validation of α-synuclein in L1CAM-immunocaptured exosomes as a biomarker for the stratification of Parkinsonian syndromes, Mov. Disord. 36, 2663 (2021).
  16. M. O. Gonçalves, J. F. Di Iorio, G. V. Marin, P. Meneghetti, N. G. S. Negreiros, and A. C. Torrecilhas, Extracellular vesicles, in Extracellular Vesicles from Basic Research to Clinical Applications, Current Topics in Membranes, edited by A. C. Torrecilhas (Academic Press, Cambridge, 2024), Vol. 94, pp. 1–31.
  17. K. Abhange, A. Makler, Y. Wen, N. Ramnauth, W. Mao, W. Asghar, and Y. Wan, Small extracellular vesicles in cancer, Bioact. Mater. 6, 3705 (2021).
  18. K. D. Brett, N. Z. Nugent, N. K. Fraser, V. M. Bhopale, M. Yang, and S. R. Thom, Microparticle and interleukin-1β production with human simulated compressed air diving, Sci. Rep. 9, 13320 (2019).
  19. J. H. W. Distler, D. S. Pisetsky, L. C. Huber, J. R. Kalden, S. Gay, and O. Distler, Microparticles as regulators of inflammation: Novel players of cellular crosstalk in the rheumatic diseases, Arthritis Rheum. 52, 3337 (2005).
  20. D. Ruhela, V. M. Bhopale, M. Yang, K. Yu, E. Weintraub, A. Greenblatt, and S. R. Thom, Blood-borne and brain-derived microparticles in morphine-induced anti-nociceptive tolerance, Brain Behav. Immun. 87, 465 (2020).
  21. D. Ruhela, V. M. Bhopale, S. Kalakonda, and S. R. Thom, Astrocyte-derived microparticles initiate a neuroinflammatory cycle due to carbon monoxide poisoning, Brain Behav. Immun. Health 18, 100398 (2021).
  22. C. Ciardiello, R. Migliorino, A. Leone, and A. Budillon, Large extracellular vesicles: Size matters in tumor progression, Cytokine Growth Factor Rev. 51, 69 (2020).
  23. Z. Varga, B. Fehér, D. Kitka, A. Wacha, A. Bóta, S. Berényi, V. Pipich, and J.-L. Fraikin, Size measurement of extracellular vesicles and synthetic liposomes: The impact of the hydration shell and the protein corona, Colloids Surf. B 192, 111053 (2020).
  24. M. F. Baietti, Z. Zhang, E. Mortier, A. Melchior, G. Degeest, A. Geeraerts, Y. Ivarsson, F. Depoortere, C. Coomans, E. Vermeiren, P. Zimmermann, and G. David, Syndecan-syntenin-alix regulates the biogenesis of exosomes, Nat. Cell Biol. 14, 677 (2012).
  25. M. Ostrowski, N. B. Carmo, S. Krumeich, I. Fanget, G. Raposo, A. Savina, C. F. Moita, K. Schauer, A. N. Hume, R. P. Freitas, B. Goud, P. Benaroch, N. Hacohen, M. Fukuda, C. Desnos, M. C. Seabra, F. Darchen, S. Amigorena, L. F. Moita, and C. Thery, Rab27a and Rab27b control different steps of the exosome secretion pathway, Nat. Cell Biol. 12, 19 (2010).
  26. F. K. Fordjour, C. Guo, Y. Ai, G. G. Daaboul, and S. J. Gould, A shared, stochastic pathway mediates exosome protein budding along plasma and endosome membranes, J. Biol. Chem. 298, 102394 (2022).
  27. M. Mathieu, N. Nevo, M. Jouve, J. I. Valenzuela, M. Maurin, F. J. Verweij, R. Palmulli, D. Lankar, F. Dingli, D. Loew, E. Rubinstein, G. Boncompain, F. Perez, and C. Thery, Specificities of exosome versus small ectosome secretion revealed by live intracellular tracking of CD63 and CD9, Nat. Commun. 12, 4389 (2021).
  28. T. Matsui, F. Osaki, S. Hiragi, Y. Sakamaki, and M. Fukuda, Alix and ceramide differentially control polarized small extracellular vesicle release from epithelial cells, EMBO Rep. 22, e51475 (2021).
  29. J. Kowal, G. Arras, M. Colombo, M. Jouve, J. P. Morath, B. Primdal-Bengtson, F. Dingli, D. Loew, M. Tkach, and C. Théry, Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes, Proc. Natl. Acad. Sci. USA 113, E968 (2016).
  30. M. Dieudé, et al., The 20s proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection, Sci. Transl. Med. 7, 318ra200 (2015).
  31. M. Hristov, W. Erl, S. Linder, and P. C. Weber, Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro, Blood 104, 2761 (2004).
  32. L. Ma, Y. Li, J. Peng, D. Wu, X. Zhao, Y. Cui, L. Chen, X. Yan, Y. Du, and L. Yu, Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration, Cell Res. 25, 24 (2015).
  33. X. Zhao, Y. Lei, J. Zheng, J. Peng, Y. Li, L. Yu, and Y. Chen, Identification of markers for migrasome detection, Cell Discov. 5, 27 (2019).
  34. Y. Huang, B. Zucker, S. Zhang, S. Elias, Y. Zhu, H. Chen, T. Ding, Y. Li, Y. Sun, J. Lou, M. M. Kozlov, and L. Yu, Migrasome formation is mediated by assembly of micron-scale tetraspanin macrodomains, Nat. Cell Biol. 21, 991 (2019).
  35. V. R. Minciacchi, C. Spinelli, M. Reis-Sobreiro, L. Cavallini, S. You, M. Zandian, X. Li, R. Mishra, P. Chiarugi, R. M. Adam, E. M. Posadas, G. Viglietto, M. R. Freeman, E. Cocucci, N. A. Bhowmick, and D. Di Vizio, MYC mediates large oncosome-induced fibroblast reprogramming in prostate cancer, Cancer Res. 77, 2306 (2017).
  36. D. Di Vizio, M. Morello, A. C. Dudley, P. W. Schow, R. M. Adam, S. Morley, D. Mulholland, M. Rotinen, M. H. Hager, L. Insabato, M. A. Moses, F. Demichelis, M. P. Lisanti, H. Wu, M. Klagsbrun, N. A. Bhowmick, M. A. Rubin, C. D’Souza-Schorey, and M. R. Freeman, Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease, Am. J. Pathol. 181, 1573 (2012).
  37. A. Callan-Jones and P. Bassereau, Curvature-driven membrane lipid and protein distribution, Curr. Opin. Solid State Mater. Sci. 17, 143 (2013).
  38. M. M. Kozlov and J. W. Taraska, Generation of nanoscopic membrane curvature for membrane trafficking, Nat. Rev. Mol. Cell Biol. 24, 63 (2023).
  39. J. Derganc and A. Čopič, Membrane bending by protein crowding is affected by protein lateral confinement, Biochim. Biophys. Acta 1858, 1152 (2016).
  40. J. C. Stachowiak, E. M. Schmid, C. J. Ryan, H. S. Ann, D. Y. Sasaki, M. B. Sherman, P. L. Geissler, D. A. Fletcher, and C. C. Hayden, Membrane bending by protein-protein crowding, Nat. Cell Biol. 14, 944 (2012).
  41. D. J. Busch, J. R. Houser, C. C. Hayden, M. B. Sherman, E. M. Lafer, and J. C. Stachowiak, Intrinsically disordered proteins drive membrane curvature, Nat. Commun. 6, 7875 (2015).
  42. S. Liese and A. Carlson, Membrane shape remodeling by protein crowding, Biophys. J. 120, 2482 (2021).
  43. V. T. Ruhoff, G. Moreno-Pescador, W. Pezeshkian, and P. M. Bendix, Strength in numbers: Effect of protein crowding on the shape of cell membranes, Biochem. Soc. Trans. 50, 1257 (2022).
  44. H. Alimohamadi and P. Rangamani, Modeling membrane curvature generation due to membrane–protein interactions, Biomolecules 8, 120 (2018).
  45. N. Walani, J. Torres, and A. Agrawal, Endocytic proteins drive vesicle growth via instability in high membrane tension environment, Proc. Natl. Acad. Sci. USA 112, E1423 (2015).
  46. J. E. Hassinger, G. Oster, D. G. Drubin, and P. Rangamani, Design principles for robust vesiculation in clathrin-mediated endocytosis, Proc. Natl. Acad. Sci. USA 114, E1118 (2017).
  47. R. Ma and J. Berro, Endocytosis against high turgor pressure is made easier by partial coating and freely rotating base, Biophys. J. 120, 1625 (2021).
  48. K. Xiao, C.-X. Wu, and R. Ma, Vesiculation mechanisms mediated by anisotropic proteins, Phys. Rev. Res. 5, 023176 (2023).
  49. B. Alberts, A. Johnson, J. Lewis, D. Morgan, M. Raff, K. Roberts, and P. Walter, Molecular Biology of the Cell (Garland Science, New York, 2015).
  50. J. C.-H. Kuo, J. G. Gandhi, R. N. Zia, and M. J. Paszek, Physical biology of the cancer cell glycocalyx, Nat. Phys. 14, 658 (2018).
  51. S. Weinbaum, J. M. Tarbell, and E. R. Damiano, The structure and function of the endothelial glycocalyx layer, Annu. Rev. Biomed. Eng. 9, 121 (2007).
  52. L. Möckl, The emerging role of the mammalian glycocalyx in functional membrane organization and immune system regulation, Front. Cell Dev. Biol. 8, 253 (2020).
  53. C. R. Shurer, J. C.-H. Kuo, L. M. Roberts, J. G. Gandhi, M. J. Colville, T. A. Enoki, H. Pan, J. Su, J. M. Noble, M. J. Hollander, J. P. O’Donnell, R. Yin, K. Pedram, L. Möckl, L. F. Kourkoutis, W. Moerner, C. R. Bertozzi, G. W. Feigenson, H. L. Reesink, and M. J. Paszek, Physical principles of membrane shape regulation by the glycocalyx, Cell 177, 1757 (2019).
  54. J. C.-H. Kuo and M. J. Paszek, Glycocalyx curving the membrane: Forces emerging from the cell exterior, Annu. Rev. Cell Dev. Biol. 37, 257 (2021).
  55. S. Gollapudi, S. Jamal, A. Kamatar, F. Yuan, L. Wang, E. M. Lafer, B. Belardi, and J. C. Stachowiak, Steric pressure between glycosylated transmembrane proteins inhibits internalization by endocytosis, Proc. Natl. Acad. Sci. USA 120, e2215815120 (2023).
  56. R. Alert and J. Casademunt, Bleb nucleation through membrane peeling, Phys. Rev. Lett. 116, 068101 (2016).
  57. R. Alert, J. Casademunt, J. Brugués, and P. Sens, Model for probing membrane-cortex adhesion by micropipette aspiration and fluctuation spectroscopy, Biophys. J. 108, 1878 (2015).
  58. F. Y. Lim, K.-H. Chiam, and L. Mahadevan, The size, shape, and dynamics of cellular blebs, Europhys. Lett. 100, 28004 (2012).
  59. W. Strychalski and R. D. Guy, A computational model of bleb formation, Math. Med. Biol. 30, 115 (2013).
  60. W. Strychalski and R. D. Guy, Intracellular pressure dynamics in blebbing cells, Biophys. J. 110, 1168 (2016).
  61. E. K. Paluch and E. Raz, The role and regulation of blebs in cell migration, Curr. Opin. Cell Biol. 25, 582 (2013).
  62. G. Charras and E. Paluch, Blebs lead the way: How to migrate without lamellipodia, Nat. Rev. Mol. Cell Biol. 9, 730 (2008).
  63. R. Merkel, R. Simson, D. A. Simson, M. Hohenadl, A. Boulbitch, E. Wallraff, and E. Sackmann, A micromechanic study of cell polarity and plasma membrane cell body coupling in dictyostelium, Biophys. J. 79, 707 (2000).
  64. E. S. Welf, C. E. Miles, J. Huh, E. Sapoznik, J. Chi, M. K. Driscoll, T. Isogai, J. Noh, A. D. Weems, T. Pohlkamp, K. Dean, R. Fiolka, A. Mogilner, and G. Danuser, Actin-membrane release initiates cell protrusions, Dev. Cell 55, 723 (2020).
  65. J. Dai and M. P. Sheetz, Membrane tether formation from blebbing cells, Biophys. J. 77, 3363 (1999).
  66. A. Diz-Muñoz, M. Krieg, M. Bergert, I. Ibarlucea-Benitez, D. J. Muller, E. Paluch, and C.-P. Heisenberg, Control of directed cell migration in vivo by membrane-to-cortex attachment, PLoS Biol. 8, e1000544 (2010).
  67. A. Paraschiv, T. J. Lagny, C. V. Campos, E. Coudrier, P. Bassereau, and A. Šarić, Influence of membrane-cortex linkers on the extrusion of membrane tubes, Biophys. J. 120, 598 (2021).
  68. M. Sheetz, Cell control by membrane-cytoskeleton adhesion, Nat. Rev. Mol. Cell Biol. 2, 392 (2001).
  69. F.-C. Tsai, G. Guérin, J. Pernier, and P. Bassereau, Actin-membrane linkers: Insights from synthetic reconstituted systems, Eur. J. Cell Biol. 103, 151402 (2024).
  70. M. Tsujioka, S. Yumura, K. Inouye, H. Patel, M. Ueda, and S. Yonemura, Talin couples the actomyosin cortex to the plasma membrane during rear retraction and cytokinesis, Proc. Natl. Acad. Sci. USA 109, 12992 (2012).
  71. S. Tsukita and S. Yonemura, Cortical actin organization: Lessons from ERM (ezrin/radixin/moesin) proteins*, J. Biol. Chem. 274, 34507 (1999).
  72. R. G. Fehon, A. I. McClatchey, and A. Bretscher, Organizing the cell cortex: The role of ERM proteins, Nat. Rev. Mol. Cell Biol. 11, 276 (2010).
  73. E. Korkmazhan and A. R. Dunn, The membrane-actin linker ezrin acts as a sliding anchor, Sci. Adv. 8, eabo2779 (2022).
  74. K. Xiao, S. Park, J. C. Stachowiak, and P. Rangamani, Biophysical modeling of membrane curvature generation and curvature sensing by the glycocalyx, Proc. Natl. Acad. Sci. USA 122, e2418357122 (2025).
  75. K. Xiao and P. Rangamani, Glycocalyx-induced formation of membrane tubes, Biophys. J. 124, 1631 (2025).
  76. C. L. Hattrup and S. J. Gendler, Structure and function of the cell surface (tethered) mucins, Annu. Rev. Physiol. 70, 431 (2008).
  77. Y. Jung, I. Riven, S. W. Feigelson, E. Kartvelishvily, K. Tohya, M. Miyasaka, R. Alon, and G. Haran, Three-dimensional localization of T-cell receptors in relation to microvilli using a combination of superresolution microscopies, Proc. Natl. Acad. Sci. USA 113, 5916 (2016).
  78. G. Kesavan, F. W. Sand, T. U. Greiner, J. K. Johansson, S. Kobberup, X. Wu, C. Brakebusch, and H. Semb, Cdc42-mediated tubulogenesis controls cell specification, Cell 139, 791 (2009).
  79. M. Kesimer, C. Ehre, K. A. Burns, C. W. Davis, J. K. Sheehan, and R. J. Pickles, Molecular organization of the mucins and glycocalyx underlying mucus transport over mucosal surfaces of the airways, Mucosal Immunol. 6, 379 (2013).
  80. S. Makabe, T. Naguro, and T. Stallone, Oocyte–follicle cell interactions during ovarian follicle development, as seen by high resolution scanning and transmission electron microscopy in humans, Microsc. Res. Tech. 69, 436 (2006).
  81. S. P. Evanko, M. I. Tammi, R. H. Tammi, and T. N. Wight, Hyaluronan-dependent pericellular matrix, Adv. Drug Delivery Rev. 59, 1351 (2007).
  82. B. Button, L.-H. Cai, C. Ehre, M. Kesimer, D. B. Hill, J. K. Sheehan, R. C. Boucher, and M. Rubinstein, A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia, Science 337, 937 (2012).
  83. J. Richard Bennett, Jr., T. Järvelä, P. Engelhardt, L. Kostamovaara, P. Sparks, O. Carpén, O. Turunen, and A. Vaheri, Mucin MUC1 is seen in cell surface protrusions together with ezrin in immunoelectron tomography and is concentrated at tips of filopodial protrusions in MCF-7 breast carcinoma cells, J. Histochem. Cytochem. 49, 67 (2001).
  84. V. Koistinen, R. Kärnä, A. Koistinen, A. Arjonen, M. Tammi, and K. Rilla, Cell protrusions induced by Hyaluronan Synthase 3 (HAS3) resemble mesothelial microvilli and share cytoskeletal features of filopodia, Exp. Cell Res. 337, 179 (2015).
  85. C. Hiergeist and R. Lipowsky, Elastic properties of polymer-decorated membranes, J. Phys. II France 6, 1465 (1996).
  86. R. Lipowsky, Bending of membranes by anchored polymers, Europhys. Lett. 30, 197 (1995).
  87. M. Breidenich, R. R. Netz, and R. Lipowsky, The shape of polymer-decorated membranes, Europhys. Lett. 49, 431 (2000).
  88. T. Bickel, C. Jeppesen, and C. Marques, Local entropic effects of polymers grafted to soft interfaces, Eur. Phys. J. E 4, 33 (2001).
  89. Y. W. Kim and W. Sung, Membrane curvature induced by polymer adsorption, Phys. Rev. E 63, 041910 (2001).
  90. F. Campelo and A. Hernández-Machado, Model for curvature-driven pearling instability in membranes, Phys. Rev. Lett. 99, 088101 (2007).
  91. F. Campelo and A. Hernández-Machado, Polymer-induced tubulation in lipid vesicles, Phys. Rev. Lett. 100, 158103 (2008).
  92. M. Werner and J. U. Sommer, Polymer-decorated tethered membranes under good- and poor-solvent conditions, Eur. Phys. J. E 31, 383 (2010).
  93. S. Kutti Kandy and R. Radhakrishnan, Crowding-induced membrane remodeling: Interplay of membrane tension, polymer density, architecture, Biophys. J. 121, 3674 (2022).
  94. G. Charras, A short history of blebbing, J. Microsc. 231, 466 (2008).
  95. J.-Y. Tinevez, U. Schulze, G. Salbreux, J. Roensch, J.-F. Joanny, and E. Paluch, Role of cortical tension in bleb growth, Proc. Natl. Acad. Sci. USA 106, 18581 (2009).
  96. A. Mahapatra, S. A. Malingen, and P. Rangamani, Interplay between cortical adhesion and membrane bending regulates microparticle formation, bioRxiv 2024.02.07.579325 (2024).
  97. P. Canham, The minimum energy of bending as a possible explanation of the biconcave shape of the human red blood cell, J. Theor. Biol. 26, 61 (1970).
  98. W. Helfrich, Elastic properties of lipid bilayers—Theory and possible experiments, Z. Naturforsch. C 28, 693 (1973).
  99. A. Maitra, P. Srivastava, M. Rao, and S. Ramaswamy, Activating membranes, Phys. Rev. Lett. 112, 258101 (2014).
  100. N. Gov, A. G. Zilman, and S. Safran, Cytoskeleton confinement and tension of red blood cell membranes, Phys. Rev. Lett. 90, 228101 (2003).
  101. E. A. Evans and R. Skalak, Mechanics and Thermodynamics of Biomembranes (CRC Press, Boca Raton, 1980).
  102. H. Hägerstrand, V. Kralj-Iglič, M. Bobrowska-Hägerstrand, and A. Iglič, Membrane skeleton detachment in spherical and cylindrical microexovesicles, Bull. Math. Biol. 61, 1019 (1999).
  103. A. Iglič, A possible mechanism determining the stability of spiculated red blood cells, J. Biomech. 30, 35 (1997).
  104. R. Waugh, Elastic energy of curvature-driven bump formation on red blood cell membrane, Biophys. J. 70, 1027 (1996).
  105. P. J. Flory, Thermodynamics of high polymer solutions, J. Chem. Phys. 9, 660 (1941).
  106. M. L. Huggins, Solutions of long chain compounds, J. Chem. Phys. 9, 440 (1941).
  107. A. Winter, Y. Liu, A. Ziepke, G. Dadunashvili, and E. Frey, Phase separation on deformable membranes: Interplay of mechanical coupling and dynamic surface geometry, Phys. Rev. E 111, 044405 (2025).
  108. H. Kramers, Brownian motion in a field of force and the diffusion model of chemical reactions, Physica 7, 284 (1940).
  109. E. Evans, Probing the relation between force-lifetime-and chemistry in single molecular bonds, Annu. Rev. Biophys. 30, 105 (2001).
  110. A. Veksler and N. S. Gov, Calcium-actin waves and oscillations of cellular membranes, Biophys. J. 97, 1558 (2009).
  111. R. Shlomovitz and N. S. Gov, Membrane waves driven by actin and myosin, Phys. Rev. Lett. 98, 168103 (2007).
  112. T. Frohoff-Hülsmann and U. Thiele, Nonreciprocal Cahn-Hilliard model emerges as a universal amplitude equation, Phys. Rev. Lett. 131, 107201 (2023).
  113. E. B. Zhulina, T. M. Birshtein, and O. V. Borisov, Curved polymer and polyelectrolyte brushes beyond the Daoud-Cotton model, Eur. Phys. J. E 20, 243 (2006).
  114. A. Veksler and N. S. Gov, Phase transitions of the coupled membrane-cytoskeleton modify cellular shape, Biophys. J. 93, 3798 (2007).
  115. C. Tozzi, N. Walani, and M. Arroyo, Out-of-equilibrium mechanochemistry and self-organization of fluid membranes interacting with curved proteins, New J. Phys. 21, 093004 (2019).
  116. R. Lipowsky, Domain-induced budding of fluid membranes, Biophys. J. 64, 1133 (1993).
  117. J. Liu, M. Kaksonen, D. G. Drubin, and G. Oster, Endocytic vesicle scission by lipid phase boundary forces, Proc. Natl. Acad. Sci. USA 103, 10277 (2006).
  118. J.-M. Allain, C. Storm, A. Roux, M. Ben Amar, and J.-F. Joanny, Fission of a multiphase membrane tube, Phys. Rev. Lett. 93, 158104 (2004).
  119. L. Foret, Shape and energy of a membrane bud induced by protein coats or viral protein assembly, Eur. Phys. J. E 37, 42 (2014).
  120. Z. Shi and T. Baumgart, Membrane tension and peripheral protein density mediate membrane shape transitions, Nat. Commun. 6, 5974 (2015).
  121. R. Phillips, T. Ursell, P. Wiggins, and P. Sens, Emerging roles for lipids in shaping membrane-protein function, Nature (London) 459, 379 (2009).
  122. T. Baumgart, S. Hess, and W. Webb, Imaging coexisting fluid domains in biomembrane models coupling curvature and line tension, Nature (London) 425, 821 (2003).
  123. R. Lipowsky, Budding of membranes induced by intramembrane domains, J. Phys. II France 2, 1825 (1992).
  124. D. Bracha, E. Karzbrun, G. Shemer, P. A. Pincus, and R. H. Bar-Ziv, Entropy-driven collective interactions in DNA brushes on a biochip, Proc. Natl. Acad. Sci. USA 110, 4534 (2013).
  125. L. Foret and P. Sens, Kinetic regulation of coated vesicle secretion, Proc. Natl. Acad. Sci. USA 105, 14763 (2008).
  126. J. Paturej, S. S. Sheiko, S. Panyukov, and M. Rubinstein, Molecular structure of bottlebrush polymers in melts, Sci. Adv. 2, e1601478 (2016).
  127. J. G. Gandhi, D. L. Koch, and M. J. Paszek, Equilibrium modeling of the mechanics and structure of the cancer glycocalyx, Biophys. J. 116, 694 (2019).
  128. M. C. Cross and P. C. Hohenberg, Pattern formation outside of equilibrium, Rev. Mod. Phys. 65, 851 (1993).
  129. M. A. Antonyak, B. Li, L. K. Boroughs, J. L. Johnson, J. E. Druso, K. L. Bryant, D. A. Holowka, and R. A. Cerione, Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells, Proc. Natl. Acad. Sci. USA 108, 4852 (2011).
  130. T. Wang, D. M. Gilkes, N. Takano, L. Xiang, W. Luo, C. J. Bishop, P. Chaturvedi, J. J. Green, and G. L. Semenza, Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis, Proc. Natl. Acad. Sci. USA 111, E3234 (2014).
  131. V. Muralidharan-Chari, J. W. Clancy, A. Sedgwick, and C. D’Souza-Schorey, Microvesicles: Mediators of extracellular communication during cancer progression, J. Cell Sci. 123, 1603 (2010).
  132. C.-H. Lu, K. Pedram, C.-T. Tsai, T. Jones, X. Li, M. L. Nakamoto, C. R. Bertozzi, and B. Cui, Membrane curvature regulates the spatial distribution of bulky glycoproteins, Nat. Commun. 13, 3093 (2022).
  133. M. Goudarzi, T. Banisch, M. Mobin, N. Maghelli, K. Tarbashevich, I. Strate, J. van den Berg, H. Blaser, S. Bandemer, E. Paluch, J. Bakkers, I. Tolić-Nørrelykke, and E. Raz, Identification and regulation of a molecular module for bleb-based cell motility, Dev. Cell 23, 210 (2012).
  134. A. Lorentzen, J. Bamber, A. Sadok, I. Elson-Schwab, and C. J. Marshall, An ezrin-rich, rigid uropod-like structure directs movement of amoeboid blebbing cells, J. Cell Sci. 124, 1256 (2011).
  135. Y. Yanase, I. Hide, S. Mihara, Y. Shirai, N. Saito, Y. Nakata, M. Hide, and N. Sakai, A critical role of conventional protein kinase C in morphological changes of rodent mast cells, Immunol. Cell Biol. 89, 149 (2011).
  136. V. Niggli and J. Rossy, Ezrin/radixin/moesin: Versatile controllers of signaling molecules and of the cortical cytoskeleton, Int. J. Biochem. Cell Biol. 40, 344 (2008).
  137. S. Martinelli, E. J. Chen, F. Clarke, R. Lyck, S. Affentranger, J. K. Burkhardt, and V. Niggli, Ezrin/radixin/moesin proteins and flotillins cooperate to promote uropod formation in T cells, Front. Immunol. 4, 84 (2013).
  138. A. Iglič and H. Hägerstrand, Amphiphile-induced spherical microexovesicle corresponds to an extreme local area difference between two monolayers of the membrane bilayer, Med. Biol. Eng. Comput. 37, 125 (1999).
  139. E. Donath and D. Lerche, Electrostatic and structural properties of the surface of human erythrocytes. I-cell-electrophoretic studies following neuraminidase treatment, J. Electroanal. Chem. Interfacial Electrochem. 116, 41 (1980).
  140. R. Heinrich, M. Gaestel, and R. Glaser, The electric potential profile across the erythrocyte membrane, J. Theor. Biol. 96, 211 (1982).
  141. A. Iglič, M. Brumen, and S. Svetina, Determination of the inner surface potential of the erythrocyte membrane, Bioelectrochem. Bioenerg. 43, 97 (1997).
  142. D. Lerche, M. Kozlov, and V. Markin, Electrostatic free energy and spontaneous curvature of spherical charged layered membrane, Biorheology 24, 23 (1987).
  143. S. McLaughlin, The electrostatic properties of membranes, Annu. Rev. Biophys. 18, 113 (1989).
  144. M. M. Kozlov, M. Winterhalter, and D. Lerche, Elastic properties of strongly curved monolayers. Effect of electric surface charges, J. Phys. II France 2, 175 (1992).
  145. V. Kralj-Iglič and A. Iglič, A simple statistical mechanical approach to the free energy of the electric double layer including the excluded volume effect, J. Phys. II France 6, 477 (1996).
  146. E. Gongadze, A. Velikonja, Š. Perutkova, P. Kramar, A. Maček-Lebar, V. Kralj-Iglič, and A. Iglič, Ions and water molecules in an electrolyte solution in contact with charged and dipolar surfaces, Electrochim. Acta 126, 42 (2014).
  147. https://github.com/RangamaniLabUCSD/Glycocalyx_Membrane_Cortex

Outline

Information

Phys. Rev. Research 8, 013012– Published 8 January, 2026
  • Received 3 August 2025
  • Accepted 6 December 2025
Crossmark - Check for updates button
Creative Commons Logo

Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

Published by the American Physical Society

Sign In to Your Journals Account

Filter

Filter

Article Lookup

Enter a citation