Abstract
Contrary to current insulin formulations, endogenous insulin has direct access to the portal vein, regulating glucose metabolism in the liver with minimal hypoglycaemia. Here we report the synthesis of an amphiphilic diblock copolymer comprising a glucose-responsive positively charged segment and polycarboxybetaine. The mixing of this polymer with insulin facilitates the formation of worm-like micelles, achieving highly efficient absorption by the gastrointestinal tract and the creation of a glucose-responsive reservoir in the liver. Under hyperglycaemic conditions, the polymer triggers a rapid release of insulin, establishing a portal-to-peripheral insulin gradient—similarly to endogenous insulin—for the safe regulation of blood glucose. This insulin formulation exhibits a dose-dependent blood-glucose-regulating effect in a streptozotocin-induced mouse model of type 1 diabetes and controls the blood glucose at normoglycaemia for one day in non-obese diabetic mice. In addition, the formulation demonstrates a blood-glucose-lowering effect for one day in a pig model of type 1 diabetes without observable hypoglycaemia, showing promise for the safe and effective management of type 1 diabetes.
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The data that support the results of this study are available within the Article and its Supplementary Information. Source data are provided with this paper.
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Acknowledgements
This work was supported by grants from the National Key R&D Program of China (2022YFE0202200, J.W.), JDRF (2-SRA-2021-1064-M-B, Z.G.; 2-SRA-2022-1159-M-B, J.W.), the Key Project of Science and Technology Commission of Zhejiang Province (2024C03083, Z.G.; 2024C03085, J.W.), Zhejiang University’s start-up packages and the Starry Night Science Fund at Shanghai institute for Advanced Study of Zhejiang University (SN-ZJU-SIAS-009, J.W.). A.R.K. is supported by the National Center for Advancing Translational Sciences, National Institutes of Health (KL2TR002490, J.W.). The project was supported by the Clinical and Translational Science Award program of the National Center for Advancing Translational Science, National Institutes of Health (UL1TR002489, J.W.). We appreciate the help from J. Pan and D. Wu of the Research and Service Center (College of Pharmaceutical Science, Zhejiang University) for technical support, G. Z. and Y. Zhang (Cryo-EM centre, Zhejiang University) for processing the samples for electron microscopy and D. Xu, M. Zhang, S. Xiong and D. Chen (Disease Simulation and Animal Model Platform of Liangzhu Laboratory) for taking care of the minipigs.
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Z.G., J.W., Y.S. and J.B.B. conceived and designed the study. K.J., Xiangqian Wei, J.Z., J.X., Xinwei Wei, Y.Z., W.L., Y.W., Y.Y., S.M. and Y.L. conducted experiments and obtained related data. X.H., S.W., Z.Z., J.Y., G.X. and Z.L. gave experimental operation and theoretical guidance of mice experiments. K.J., Xiangqian Wei, J.Z. and J.X. conducted minipigs experiments and provided theoretical support. Z.G., J.W., Y.S., K.J., J.Z., Xiangqian Wei, A.R.K., J.B.B. and J.X. analysed the data and wrote the paper.
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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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Nature Nanotechnology thanks Kåre Birkeland and Nicholas Hunt for their contribution to the peer review of this work.
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Extended data
Extended Data Fig. 1 BG-regulating effects in diabetic minipigs.
BG of diabetic minipigs treated with the insulin capsules (oral), the PPF-ins capsules (oral) or Lantus (s.c.). The insulin dose of oral formulations was set to 4.2 U/kg. The Lantus dose was set to 0.3 U/kg.
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Ji, K., Wei, X., Kahkoska, A.R. et al. An orally administered glucose-responsive polymeric complex for high-efficiency and safe delivery of insulin in mice and pigs. Nat. Nanotechnol. 19, 1880–1891 (2024). https://doi.org/10.1038/s41565-024-01764-5
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DOI: https://doi.org/10.1038/s41565-024-01764-5
