Abstract
The nuclear envelope serves as a highly regulated gateway for macromolecule exchange between the nucleus and cytoplasm in eukaryotes. Here we have developed a cell nucleus-mimicking polymeric membrane-enclosed system for long and self-regulated therapy. A polymeric nano-membrane with nanopores is conformally synthesized in situ on the surface of each insulin crystal, ensuring sustained, adjustable and zero-order drug release kinetics. Glucose- and β-hydroxybutyrate-dually sensitive microdomains are integrated into the nano-membranes. Under a normal state, the microdomains are uncharged and the channel is narrow enough to block insulin outflow. Under hyperglycaemia and ketonaemia, microdomains convert the high glucose and β-hydroxybutyrate concentration signals to the negative electric potential of membranes, widening the nanopores with rapid insulin outflow. In type 1 diabetic mice and minipigs, this system can maintain normoglycaemia for longer than 1 month and 3 weeks, respectively, with validated glucose- and β-hydroxybutyrate-triggered insulin release. Such membrane-enclosed drug crystal/powder formulation provides a broad platform for long-acting controlled release.
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Acknowledgements
This work was supported by grants from the National Key R&D Program of China (2022YFE0202200, J.W.), the Key R&D Program of Zhejiang Province (2024C03085, J.W.), the National Natural Science Foundation of China (32471374, J.W.), the Zhejiang University’s Start-up Packages, the Starry Night Science Fund at Shanghai Institute for Advanced Study of Zhejiang University (SN-ZJU-SIAS-009, J.W.), the Postdoctoral Fund of Zhejiang Province (ZJ2023044, J.X.) and the Postdoctoral Fellowship Program of CPSF (GZB20240669, L.L.). We thank J. Pan in the Research and Service Center, College of Pharmaceutical Sciences, Zhejiang University, for performing NMR spectrometry for structure elucidation and G. Zhu, D. Song and L. Wu in the Center of Cryo-Electron Microscopy (CCEM), Zhejiang University, for their technical assistance on scanning electron microscopy, energy-dispersive X-ray spectroscopy mapping and cryo-transmission electron microscopy. We appreciate the help from D. Guo (Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine) for slicing and staining skin tissue, X. Zhao (Bio-ultrastructure Analysis Lab of Analysis Center of Agrobiology and Environmental Sciences, Zhejiang University) for frozen slicing of materials, C. Sun and L. Mao (Analysis Center of Agrobiology and Environmental Sciences, Zhejiang University) for MALDI-TOF mass analysis and FTIR spectrum, as well as D. Xu, M. Zhang, J. Chen and S. Xiong (Animal Center, Zhejiang University) for taking care of pigs.
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J.X. and Y.Z. contributed equally to this work. Z.G., J.W. and S.Z. conceived and designed the study. J.X., Y.Z., J.Z., W.L., K.J., G.X., P.W., X.W., S.M., L.L., Y.Y., F.L. and Y.M. conducted the experiments and obtained related data. J.Z. and J.W. gave experimental operation teaching and theoretical guidance on host response evaluation. Y.W., J.Y. and Z.G. designed and drew the schematic of this article. J.X., Y.Z., J.W., J.B.B., J.G. and Z.G. analysed the data and wrote the paper.
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Z.G. and J.W. have applied for patents related to this study (PCT/CN2024/081997 and 2024102784888). Z.G. is the co-founder of Zenomics Inc., Zcapsule Inc. and μZen Inc. The other authors declare no competing interests.
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Xu, J., Zhang, Y., Zhao, S. et al. A bioinspired polymeric membrane-enclosed insulin crystal achieves long-term, self-regulated drug release for type 1 diabetes therapy. Nat. Nanotechnol. 20, 697–706 (2025). https://doi.org/10.1038/s41565-025-01860-0
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DOI: https://doi.org/10.1038/s41565-025-01860-0
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