Perry Research Group


Complex Coacervates as Biomimetic Materials

On Chip Laue

General schematic of molecular architectures for the formation of coacervates and structured coacervate domains. Specific molecular interactions (i.e., charge, hydrophobicity, hydrogen bonding) can be incorporated through the addition of different amino acid residues or other functionalities (not shown).

Living cells have evolved sophisticated inter- and intracellular organization, compartmentalization, transport, and signaling that are very challenging to reproduce synthetically. The functions of proteins and other macromolecules are dependent on both their individual structures, as well as the properties of the surrounding medium (i.e., viscosity, crowding, and other bulk phenomena, as well as direct molecular interactions). However, much of our understanding of the function and stability of biomolecules has been obtained in the absence of such effects, and has adversely affected the development of stabilized biomolecules for applications such as sensors, catalysis, and biomedicine. For instance, the storage and transportation of biomolecule-based vaccines requires refrigeration to maintain efficacy, while nature is able to stabilize proteins at physiological temperatures and higher.

One of the major challenges associated with the study of biological macromolecules is relating data obtained in the lab to the natural stability and activity of molecules in the crowded and confined intracellular environment. Functional enzyme studies, for instance, are typically performed in a dilute solution to minimize nonspecific interactions between molecules, while the actual in vivo environment contains ~20-40% protein by mass. Although the concentration of any single protein species may not be high, the total protein concentration can cause significant increases in the free energy of the solution compared to the dilute case. This increase in free energy is typically associated with decreases in entropy due to crowding. However, enthalpic effects related to chemical interactions with the environment may also be significant, but are far less studied.

Both theory and experiments have described the effects of crowding and confinement on the stability, folding, and activity of enzymes. Smaller, more compact states will be stabilized, consequently favoring or disfavoring subsequent reaction steps. Crowding also plays a significant role in driving the association of larger macromolecular assemblies and disfavoring denaturation. For instance, crowding increases the renaturation rate of DNA by 1 – 2 orders of magnitude, drives the association of 70S ribosomes from 30S and 50S particles, favors actin filament growth, and has been used to explain the need for molecular chaperones. Recently, confinement was also shown to play a role in stabilizing vaccines and antibiotics for long-term storage.

The current understanding of the specific molecular effects of crowding agents, both synthetic and natural, remains limited. This represents a major challenge in understanding and addressing the role of the environment surrounding a particular biomolecule. Commonly used polymers such as polyethylene glycol (PEG), dextran, and Ficoll, and related aqueous two-phase system (ATPS) strategies are unable to recapitulate the chemical composition of the cell interior. Unfortunately, using proteins directly as crowding agents, either in purified form or from cellular extracts, can result in unintended interactions. Thus, to develop an effective crowding medium, it is critical to identify and understand the possible interactions between the encapsulated biomolecule and the background matrix.

Specific molecular interactions such as electrostatics, hydrogen bonding, van der Waals forces, and preferential solvation result in enthalpic contributions to protein stability and/or activity. While individual effects from these interactions may be small, the synergy from a large number of combined effects can become significant, particularly given the degree of crowding present within intracellular spaces. Analysis and control of variations in biomolecule stability and activity as a function of the composition of the surrounding medium will enable identification of hierarchies of molecular interactions so that the complexity of the environment can be tailored to fit the needs of a particular experiment or application.

The most common model environments used for functional studies of biomolecules utilize polymers in solution to mimic crowding, and compartmentalization created by self-assembled vesicles or polymersomes. Creating a platform that combines both of these effects has remained a challenge for a variety of reasons including the impermeability of many lipid or polymer membranes to solutes, and the harsh solvent conditions associated with the assembly of many synthetic polymer systems. We are investigating a strategy utilizing complex coacervation to drive the membraneless sequestration and organization of biomolecules and biomolecular networks within a biomimetic intracellular environment where complex molecular interactions can be built in by design.

Complex coacervation is a phase separation phenomenon resulting from the electrostatic complexation of oppositely-charged polyelectrolytes. The resultant coacervate is a dense, polymer-rich liquid retaining both water and salt, and are common in everyday life applications such as processed food, cosmetics, Kindle® displays, and the natural adhesives used by sessile marine animals. Molecular design can be coupled with coacervation, linking polyelectrolyte domains to neutral polymer blocks to stabilize microphase separation of coacervate domains (see Figure) into structures associated with traditional block copolymers (i.e., micelles, rods, bicontinuous). Both hydrophobic and hydrophilic molecules can be loaded into these coacervate domains, facilitating drug delivery and diagnostics. Emerging experience has shown that polypeptide-based coacervation produces a dense amino acid-rich phase that closely mimics protein concentrations within cells and is an effective medium for protein encapsulation and stabilization.




  1. I. Ramírez Marrero, L. Boudreau, R. Gutzler, N. Kaiser, B. von Vacano, R. Konradi, S.L. Perry, "Decoupling the Effects of Charge Density and Hydrophobicity on the Phase Behavior and Viscoelasticity of Complex Coacervates," Macromolecules, (2024), 57(10), 4680-4694. [PDF]
  2. A. Sathyavageeswaran, J. Bonesso Sabadini, S.L. Perry, "Self-Assembling Polypeptides in Complex Coacervation," Accounts of Chemical Research, (2024), 57(3), 386-398. [PDF]
  3. P.U. Joshi, C. Decker, X. Zeng, A. Sathyavageeswaran, S.L. Perry, C.L. Heldt, "Design Rules for the Sequestration of Viruses into Polypeptide Complex Coacervates," Biomacromolecules, (2024), 25(2), 741-753. [PDF]
  4. J. Madinya, H. Tjo, X. Meng, I.A. Ramírez Marrero, C.E. Sing, S.L. Perry, "Surface Charge Density and Steric Repulsion in Polyelectrolyte-Surfactant Coacervation," Macromolecules, (2023), 56(11), 3973-3988. [PDF]
  5. J. Liu, S.L. Perry, B.Z. Tang, M.V. Tirrell, "Liquid Capsules for Gastrointestinal Drug Delivery," Matter, (2022), 5, 3107-3019 (Preview article). [PDF]
  6. A.R. Johnston, E.D. Minckler, M.C.J. Shockley, L.N. Matsushima, S.L. Perry, A.L. Ayzner, "Conjugated Polyelectrolyte-Based Complex Fluids as Aqueous Exciton Transport Networks," Angewandte Chemie International Edition, (2022), 61(20), e202117759. [PDF]
  7. J. Sun, J.D. Schiffman, S.L. Perry, "Linear Viscoelasticity and Time–Alcohol Superposition of Chitosan/Hyaluronic Acid Complex Coacervates," ACS Applied Polymer Materials, (2022), 4(3), 1617-1625. [PDF]
  8. M. Lee, S.L. Perry, R.C. Hayward, "Complex Coacervation of Polymerized Ionic Liquids in Non-Aqueous Solvents," ACS Polymers Au, (2021), 1(2), 100–106. [PDF]
  9. X. Meng, Y. Du, Y. Liu, E.B. Coughlin, S.L. Perry, J.D. Schiffman, "Electrospinning Fibers from Oligomeric Complex Coacervates: No Chain Entanglements Needed," Macromolecules, (2021), 54, 5033-5042. [PDF]
  10. A.R. Johnston, S.L. Perry, A.L. Ayzner, "Associative Phase Separation of Aqueous π-Conjugated Polyelectrolytes Couples Photophysical and Mechanical Properties," Chemistry of Materials, (2021) 33(4), 1116-1129. [PDF]
  11. W.C. Blocher McTigue, S.L. Perry, "Incorporation of Proteins into Complex Coacervates," Methods in Enzymology, (2021) 646, 277-306. [PDF]
  12. X. Mi, W.C. Blocher McTigue, P.U. Joshi, M.K. Bunker, C.L. Heldt, S.L. Perry, "Thermostabilization of Viruses via Complex Coacervation," Biomaterials Science, (2020), 8, 7082-7092. [PDF]
  13. Highlighted in the Biomaterials Science themed collection on Emerging Investigators.
    Highlighted in the 2020 Biomaterials Science Most Popular themed collection.

  14. Y. Liu, C.F. Santa Chalarca, R.N. Carmean, R.A. Olson, J. Madinya, B.S. Sumerlin, C.E. Sing, T. Emrick, S.L. Perry, "Effect of Polymer Chemistry on the Linear Viscoelasticity of Polyelectrolyte Complexes," Macromolecules, (2020), 53(18), 7851-7864. [PDF]
  15. W.C. Blocher McTigue, E. Voke, L.W. Chang, S.L. Perry, "The Benefit of Poor Mixing: Kinetics of Coacervation," Physical Chemistry Chemical Physics, (2020) 22, 20643-20657. [PDF]
  16. W.C. Blocher McTigue, S.L. Perry, "Protein Encapsulation using Complex Coacervates: What Nature has to Teach Us," Small, (2020), 16(27), 1907671. [PDF]
  17. C.E. Sing, S.L. Perry, "Recent Progress in the Science of Complex Coacervation," Soft Matter, (2020), 16, 2885-2914. [PDF]
  18. Highlighted in the 2020 Soft Matter Most Popular themed collection.

  19. S.L. Perry, D.J. McClements, "Recent Advances in Encapsulation, Protection, and Oral Delivery of Bioactive Proteins and Peptides using Colloidal Systems," Molecules, (2020), 25(5), 1161. [PDF]
  20. J. Madinya, L.W. Chang, S.L. Perry, C.E. Sing, "Sequence-Dependent Self-Coacervation in High Charge-Density Polyampholytes," Mol. Syst. Des. Eng., (2020), 5, 632-644. [PDF]
  21. J. Sun, S.L. Perry, J.D. Schiffman, "Electrospinning Nanofibers from Chitosan/Hyaluronic Acid Complex Coacervates," Biomacromolecules, (2019), 20(11), 4191-4198. [PDF]
  22. I.S. Kurtz, S. Sui, X. Hao, M. Huang, S.L. Perry, J.D. Schiffman, "Bacteria-resistant, Transparent, Free-standing Films Prepared from Complex Coacervates," ACS Applied Bio Materials, (2019), 2, 3926-3933. [PDF]
  23. T.K. Lytle, L.W. Chang, N. Markiewicz, S.L. Perry, C.E. Sing, "Designing Electrostatic Interactions via Polyelectrolyte Monomer Sequence," ACS Central Science, (2019), 5, 709-718. [PDF]
  24. Highlighted in the UMass Amherst News: UMass Amherst Chemical Engineer Sarah L. Perry Helps Decode How Charge Patterns Instruct Polymer Chain Functions

  25. W.C. Blocher McTigue, S.L. Perry, "Design Rules for Encapsulating Proteins into Complex Coacervates," Soft Matter, (2019), 15, 3089-3103. [PDF]
  26. Highlighted in the Soft Matter themed collection on Emerging Investigators.

  27. S.L. Perry, "Phase Separation: Bridging Polymer Physics and Biology," Current Opinion in Colloid and Interface Science, (2019), 39, 86-97. [PDF]
  28. X. Meng, J.D. Schiffman, S.L. Perry, "Electrospinning Cargo-Containing Polyelectrolyte Complex Fibers: Correlating Molecular Interactions to Complex Coacervate Phase Behavior and Fiber Formation," Macromolecules, (2018), 51, 8821-8832. [PDF]
  29. P.M. McCall, S. Srivastava, S.L. Perry, D.R. Kovar, M.L. Gardel, M.V. Tirrell, "Partitioning and Enhanced Self-Assembly of Actin in Polypeptide Coacervates," Biophysical Journal, (2018), 114(7), 1636-1645. [PDF]
  30. Featured on the journal cover. Highlighted on the Biophysical Society Blog.

  31. L.W. Chang, T.K. Lytle, M. Radhakrishna, J.J. Madinya, J. Vélez, C.E. Sing, S.L. Perry, "Sequence and Entropy-Based Control of Complex Coacervates," Nature Communications, (2017), 8, 1273. [PDF]
  32. Highlighted in the UMass Amherst News: "UMass Amherst Researcher Makes New Bioinspired Polymers Using Electrostatic Force"
    Highlighted in the University of Illinois News: "Electrostatic force takes charge in bioinspired polymers"
    Highlighted in Nanotechnology Now: "Electrostatic force takes charge in bioinspired polymers"
    Highlighted in Electronics 360: "Bioinspired Polymers Get Their Charge From Electrostatic Force"
    Highlighted by Nanowerk: "Electrostatic force takes charge in bioinspired polymers"
    Highlighted by My Science: "Electrostatic force takes charge in bioinspired polymers"
    Highlighted by Science Newsline: "Electrostatic force takes charge in bioinspired polymers"
    Highlighted by R&D: "Electrostatic force takes charge in bioinspired polymers"
    Highlighted by EurekAlert!: "Electrostatic force takes charge in bioinspired polymers"
    Highlighted by AZO Materials: "Progress Towards Controlling Self-Assembly of Artificial Materialss"
    Highlighted by "Electrostatic force takes charge in bioinspired polymers"
    Highlighted by "UMass Engineer Makes Bioinspired Polymers with Electrostatic Force"

  33. Y. Liu, B. Momani, H.H. Winter, S.L. Perry, "Rheological Characterization of Liquid-to-Solid Transitions in Bulk Polyelectrolyte Complexes," Soft Matter, (2017), 13, 7332-7340. [PDF]
  34. B.M. Johnston, C. W. Johnston, R. A. Letteri, T.K. Lytle, C.E. Sing, T. Emrick, S.L. Perry, "The Effect of Comb Architecture on Complex Coacervation," Organic and Biomolecular Chemistry, (2017), 15, 7630-7642. [PDF]
  35. Highlighted in the Organic & Biomolecular Chemistry Blog

  36. W.C. Blocher, S.L. Perry, "Biomimetic Complex Coacervate-Based Materials for Biomedicine," WIREs Nanomedicine and Nanobiotechnology, (2017), 9(4), e1442. [PDF].
  37. X. Meng, S.L. Perry, J.D. Schiffman, "Complex Coacervation: Chemically Stable Fibers Electrospun from Aqueous Polyelectrolyte Solutions," ACS Macro Letters, (2017), 6, 505-511. [PDF]
  38. Highlighted in: Data from University of Massachusetts Advance Knowledge in Tissue Engineering, Biotech Week, June 28th, 2017.

  39. M. Radhakrishna, K. Basu, Y. Liu, R. Shamsi, S.L. Perry, C.E. Sing, "Molecular Connectivity and Correlation Effects on Polymer Coacervation," Macromolecules, (2017) 50(7), 3030–3037. [PDF]
  40. Y. Liu, H.H. Winter, S.L. Perry, "Linear Viscoelasticity of Complex Coacervates," Advances in Colloid and Interface Science, (2017) 239, 46-60. [PDF]
  41. As of July/August 2017, this highly cited paper received enough citations to place it in the top 1% of the academic field of Chemistry based on a highly cited threshold for the field and publication year (data from Essential Science Indicators).

  42. D. Priftis, L. Leon, Z. Song, S.L. Perry, K.O. Margossian, A. Tropnikova, J. Cheng, M. Tirrell, "Self-Assembly of α-Helical Polypeptides Driven by Complex Coacervation," Angewandte Chemie International Edition, (2015) 54, 11128-11132. [PDF]
  43. S.L. Perry, C.E. Sing, "PRISM-Based Theory of Complex Coacervation: Excluded Volume versus Chain Correlation," Macromolecules, (2015) 48, 5040-5053. [PDF]
  44. K.Q. Hoffmann, S.L. Perry, L. Leon, D. Priftis, M. Tirrell, J.J. de Pablo, "A Molecular View of the Role of Chirality in Charge-driven Polypeptide Complexation," Soft Matter, (2015) 11, 1525-1538. [PDF]
  45. S.L. Perry, L. Leon, K.Q. Hoffmann, M.J. Kade, D. Priftis, K.A. Black, D. Wong, R.A. Klein, C.F. Pierce, K.O. Margossian, J.K. Whitmer, J. Qin, J.J. de Pablo, and M. Tirrell, "Chirality Selected Phase Behavior in Ionic Polypeptide Complexes," Nature Communications, (2015) 6, 6052. [PDF]
  46. D.V. Krogstad, S.H. Choi, N.A. Lynd, D.J. Andrus, S.L. Perry, J.D. Gopez, C.J. Hawker, E.J. Kramer, M. Tirrell, "Small Angle Neutron Scattering Study of Complex Coacervate Micelles and Hydrogels Formed from Ionic Diblock and Triblock Copolymers," Journal of Physical Chemistry B, (2014) 118, 13011-13018. [PDF]
  47. K.A. Black, D. Priftis, S.L. Perry, J. Yip, W.Y. Byun, M. Tirrell, "Protein Encapsulation via Polypeptide Complex Coacervation," ACS Macro Letters, (2014) 3, 1088-1091. [PDF]
  48. Highlighted on the C&EN Biological and Materials News SCENE.

    Highlighted in: "Charged Polymers Package Proteins," Chemical & Engineering News, (2014) 92(45), 27.

  49. S.L. Perry, Y. Li, D. Priftis, L. Leon, M. Tirrell, "The Effect of Salt on the Complex Coacervation of Vinyl Polyelectrolytes," Polymers, (2014) 6, 1756-1772. [PDF]
  50. J. Qin, D. Priftis, R. Farina, S.L. Perry, L. Leon, J. Whitmer, K. Hoffmann, M. Tirrell, J.J. de Pablo, "Interfacial Tension of Polyelectrolyte Complex Coacervate Phases,"ACS Macro Letters, (2014) 3, 565-568. [PDF]
  51. D. Priftis, X. Xia, K.O. Margossian, S.L. Perry, L. Leon, J. Qin, J.J. de Pablo, M. Tirrell, "Ternary, Tunable Polyelectrolyte Complex Fluids Driven by Complex Coacervation," Macromolecules, (2014) 47(9), 3076-3085. [PDF]


  1. X. Meng, S.L. Perry, J.D. Schiffman, Ultra-stable Printing and Coatings using Aqueous Complex Coacervates, and Compositions and Methods Thereof, US Patent No. 10,767,060 B2, Sept. 8, 2020. [PDF]
  2. X. Meng, S.L. Perry, J.D. Schiffman, Polymer Nanofibers from Electrospinning of Complex Coacervates, and Compositions and Methods Thereof, US Patent Number 10,428,444 B2, October 1, 2019. [PDF]