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A designer minimalistic model parallels the phase-separation-mediated assembly and biophysical cues of extracellular matrix

Nature Chemistry volume 17, pages 1216–1226 (2025)Cite this article

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Abstract

The propensity for controlled liquid–liquid phase separation and subsequent directed phase transition are crucial for the coacervation-mediated assembly of extracellular matrix (ECM). This spatiotemporally controlled ECM assembly can be used to develop coacervate-based polymer assembly strategies to generate biomimetic materials that can emulate the complex structures and biophysical cues of the ECM. Inspired by the tropoelastin structure, here we develop a designer minimalistic model consisting of alternating hydrophobic moieties and covalent crosslinking domains. By increasing the valence and enhancing the interaction strength of the hydrophobic moieties, we can control the degree of the assembly to enhance the propensity for phase separation and thus emulate the extracellular coacervation process of tropoelastin, including droplet formation, coalescence and maturation. The subsequent covalent-bonding-triggered coacervate–hydrogel transition with enhanced assembly order stabilizes the phase-separated structure in the form of a heterogeneous hydrogel, thereby mimicking covalent crosslinking-derived elastin fibrillation. Furthermore, the heterogeneous hydrogel network establishes a biomimetic matrix that can effectively promote the mechanosensing of adherent stem cells.

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Fig. 1: A minimalistic model with tunable assembly order emulates the spatiotemporal assembly and associated biophysical cues of ECM for cellular regulation.
Fig. 2: Hydrophobic interactions among the grafted aromatic moieties induce the formation of stable coacervate.
Fig. 3: The increased valence of grafted hydrophobic moieties promotes the formation and stability of gelatin-based coacervates.
Fig. 4: Increased interaction strength of the hydrophobic moieties grafted onto gelatin promotes the propensity for LLPS.
Fig. 5: Post-LLPS covalent crosslinking achieves an on-demand coacervate–hydrogel transition to stabilize the phase-separated structure.
Fig. 6: Coacervation-mediated fabrication of biomimetic matrix for the regulation of stem cell behaviours.

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Data availability

The data supporting the findings from this study can be found within the paper, supplementary materials or source data files. All final CG parameters, modelled structures and MD simulation inputs/outputs for each system investigated in this study are available on Zenodo at https://doi.org/10.5281/zenodo.15111903 (ref. 90). Source data are provided with this paper.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (Key Program, grant number 52433010 to L.B.). This work was financially supported by the National Key Research and Development Program (reference 2022YFB3804403 to L.B.). This work was supported by the National Natural Science Foundation of China (grant number 52473129 to P.Z.) and the Fundamental Research Funds for the Central Universities (grant number 2023ZYGXZR096 to P.Z.). This work was also supported by the GJYC program of Guangzhou (grant number 2024D03J0004 to L.B. and P.Z.), Guangdong Basic and Applied Basic Research Foundation (grant number 2025A1515012036 to P.Z.). This work was supported by the Collaborative Research Fund from the Research Grants Council of Hong Kong (project number C5044-21G to L.B.). This work was supported by the Health and Medical Research Fund, the Food and Health Bureau, the Government of the Hong Kong Special Administrative Region (08190416 to L.B.). This work was partially supported by the Research Grants Council Areas of Excellence Scheme (reference number AoE/M402/20 to L.B. and AoE/P-705/16 to Y.W.). We thank X. Yang for valuable discussions.

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  1. These authors contributed equally: Xian Xie, Tianjie Li.

Authors and Affiliations

  1. Department of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong, P.R. China

    Xian Xie, Boguang Yang, Zhuo Li & Zhinan Yang

  2. Department of Chemistry, The Chinese University of Hong Kong, Hong Kong, P.R. China

    Xian Xie, Jiahao Wu, To Ngai & Jiang Xia

  3. Department of Physics, The Chinese University of Hong Kong, Hong Kong, P.R. China

    Tianjie Li, Yajing Qi & Yi Wang

  4. Department of Electrical and Electronic Engineering, The University of Hong Kong, Hong Kong, P.R. China

    Linjie Ma & Zhiqin Chu

  5. School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, P.R. China

    Kunyu Zhang, Pengchao Zhao & Liming Bian

  6. Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou, P.R. China

    Kunyu Zhang, Pengchao Zhao & Liming Bian

  7. Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou, P.R. China

    Kunyu Zhang, Pengchao Zhao & Liming Bian

  8. National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, P.R. China

    Kunyu Zhang, Pengchao Zhao & Liming Bian

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  1. Xian Xie
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Contributions

L.B., P.Z. and Y.W. supervised the study. X.X., L.B. and P.Z. conceived of and designed the experiments. T.L. and Y.Q. contributed to the computational experiments. L.M. contributed to the AFM experiments. J.W. contributed to the microrheological tests. X.X., T.L., L.M., J.W., Y.Q., B.Y., Z.L., Z.Y., K.Z., Z.C., T.N., J.X., Y.W., P.Z. and L.B. provided discussions and analysed the experiments. X.X. and L.B. wrote the paper. All authors contributed to the final paper.

Corresponding authors

Correspondence to Yi Wang, Pengchao Zhao or Liming Bian.

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A patent application by L.B., based on the methods presented in this paper, has been filed. The other authors declare no competing interests.

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Nature Chemistry thanks J. Andrew MacKay and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 The increased valence of hydrophobic moieties decreases the internal dynamics of coacervates.

a, Fluorescence images of the FRAP recovery of Cy5-labelled coacervates with different valences. b, FRAP measurements showing a dramatic decrease in recovery speed with increasing valence (n = 3 independent coacervates per group). Data are presented as mean values ± SD. c, Relative mean-square displacement of nanoparticles encapsulated in the Coa-Nap-L, Coa-Nap, and Coa-Nap-P coacervates. d, The water content decreased with increasing valence (n = 3 independent coacervates per group). Data are presented as mean values ± SD. Statistical analyses were performed using ordinary one-way analysis of variance (ANOVA) with Tukey’s post hoc test. Statistical significance: #P < 0.0001 (Coa-Nap-L vs. Coa-Nap), ***P = 0.0003 (Coa-Nap vs. Coa-Nap-P), #P < 0.0001 (Coa-Nap-L vs. Coa-Nap-P).

Source data

Extended Data Fig. 2 Structural and dynamic properties of the gelatin-based coacervates in MD simulations.

a-b, Specific surface area (SSA) (a), and density (b) of the complex in the last 1 µs of the 5-µs simulations. c, Average end-to-end distance of gelatin chains. d, Mean squared displacement (MSD) of gelatin chains in the x-y dimension during the last 1 µs of simulations. Diffusion coefficients of the gelatin chains are labelled on the corresponding MSD curves with a unit of 10−7 cm2/s. In all panels, shaded regions and error bars stand for the standard error of the means calculated from four replicas (n = 4). Statistical analyses were performed using ordinary one-way analysis of variance (ANOVA) with Tukey’s post hoc test. Statistical significance: #P < 0.0001.

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Supplementary information

Supplementary Information (download PDF )

Supplementary Figs. 1–33, Tables 1–4 and synthesis of compounds.

Reporting Summary (download PDF )

Supplementary Video 1 (download MP4 )

Flowability of gelatin coacervate.

Supplementary Video 2 (download MP4 )

MD simulation (run1) of Gel.

Supplementary Video 3 (download MP4 )

MD simulation (run1) of Coa-Nap-L.

Supplementary Video 4 (download MP4 )

MD simulation (run1) of Coa-Nap.

Supplementary Video 5 (download MP4 )

MD simulation (run1) of Coa-Nap-P.

Supplementary Table 1 (download XLSX )

Sequences of primers.

Source data

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Xie, X., Li, T., Ma, L. et al. A designer minimalistic model parallels the phase-separation-mediated assembly and biophysical cues of extracellular matrix. Nat. Chem. 17, 1216–1226 (2025). https://doi.org/10.1038/s41557-025-01837-5

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