Abstract
Template method offers a promising strategy for synthesizing large pore inaccessible through traditional molecular design. However, this approach has not yet been successfully implemented in molecular assemblies based on weak non-covalent interactions (NCIs), mainly because the assemblies often deviate from original structures during template-assisted syntheses, and the resulting porous structures lack the robustness to survive upon template removal. In this work, we address these challenges through choosing small biocompatible building blocks featuring multiple hydrogen-bonded sites and extensive π conjugation, enabling self-assembly into desired structure in the presence of templates and ensure structural integration upon template removal. As a result, the transformation from densely packed hydrogen-bonded crystalline materials to macroporous structure, referred to as hydrogen-bonded organic frameworks (HOFs), becomes achievable. This strategy facilitates the fabrication of highly ordered materials in single-crystal form with high physiological stability, and enhanced mass transfer. Importantly, it greatly broadens the HOF library to small, affordable, low-toxic, and clinically applicable molecules, making HOFs promising biocompatible porous substrates for bio-related applications such as enzyme immobilization. Herein, we successfully loaded trypsin into macroporous HOFs, which function as effective cellular scaffolds and promote the differentiation of peripheral blood mononuclear cells into fibrocytes, demonstrating their promising potential for biologic applications.
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The experimental data generated in this study are provided within the Article, Supplementary Information and Source Data file. All data are available from the corresponding authors upon request. Source data is available for Fig. 2 and Supplementary Figs. 2–9, 13, 15–27 in the associated source data file. Source data are provided with this paper.
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Acknowledgements
The authors gratefully acknowledge the help from Mao-Chun Hong, Yong-Sheng Liu, financial support from the CAS Youth Interdisciplinary Team (grant no. JCTD-2022-12 (T.F.L)), Joint Funds for the Innovation of Science and Technology, Fujian Province (grant no. 2024Y9623 (Z.S.Y)), Science and Technology Program of Fujian Province (grant no. 2025J011174 (Z.S.Y), grant no. 2025J011175 (Z.S.Y)), Fujian Provincial Young and Middle-aged Health Leading Talent Training Program (grant no. 2023-2839 (Z.S.Y)).
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Q.X.L. performed on the design and results analysis of all experiments and wrote the manuscript. W.Z.C. assisted in the cell experiment. X.L.Y. performed TEM characterization. Z.S.Y. and Y.Z. advised on the design and interpretation of cell experiments. A.R.M.S. edited the manuscript. T.F.L. advised on the design and interpretation of all experiments and directed the overall project.
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Nature Communications thanks Francesco Carraro, Antonio Fernandez, Yanfeng Wang and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Li, QX., Cai, WZ., Ye, XL. et al. Highly ordered macroporous hydrogen-bonded organic frameworks based on small biocompatible molecules. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67123-7
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DOI: https://doi.org/10.1038/s41467-025-67123-7
