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Synthetic beta cells for fusion-mediated dynamic insulin secretion

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Abstract

Generating artificial pancreatic beta cells by using synthetic materials to mimic glucose-responsive insulin secretion in a robust manner holds promise for improving clinical outcomes in people with diabetes. Here, we describe the construction of artificial beta cells (AβCs) with a multicompartmental 'vesicles-in-vesicle' superstructure equipped with a glucose-metabolism system and membrane-fusion machinery. Through a sequential cascade of glucose uptake, enzymatic oxidation and proton efflux, the AβCs can effectively distinguish between high and normal glucose levels. Under hyperglycemic conditions, high glucose uptake and oxidation generate a low pH (<5.6), which then induces steric deshielding of peptides tethered to the insulin-loaded inner small liposomal vesicles. The peptides on the small vesicles then form coiled coils with the complementary peptides anchored on the inner surfaces of large vesicles, thus bringing the membranes of the inner and outer vesicles together and triggering their fusion and insulin 'exocytosis'.

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Figure 1: Design and synthesis of AβCs.
Figure 2: Biochemical processes inside AβCs.
Figure 3: Membrane fusion of ISVs and OLVs after glucose metabolism.
Figure 4: In vitro insulin secretion from AβCs and in vivo type 1 diabetes treatment.

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Change history

  • 14 November 2017

    In the version of this article initially published online, the wavelength depicted at the top of Figure 2g was mislabeled as 563 nm instead of 536 nm. The error has been corrected in the PDF and HTML versions of this article.

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Acknowledgements

This work was supported by grants from the American Diabetes Association (grant no. 1-15-ACE-21 to Z.G.), Alfred P. Sloan Foundation (Sloan Research Fellowship to Z.G.), National Science Foundation (grant no. 1708620 to Z.G.) and NC TraCS, NIH's Clinical and Translational Science Award (CTSA, grant no. 1UL1TR001111) at UNC-CH. This work was performed in part at the Analytical Instrumentation Facility (AIF) at North Carolina State University, which is supported by the State of North Carolina and the National Science Foundation (grant no. 1542015). The AIF is a member of the North Carolina Research Triangle Nanotechnology Network (RTNN), a site in the National Nanotechnology Coordinated Infrastructure (NNCI). The authors also thank P. Chipman and R. Alvarado at the University of Florida's ICBR center.

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Z.C., F.S.L., J.B.B. and Z.G. designed the project; Z.C., J.W., W.S., E.A., X.Z. and Y.L. performed the experiments; Z.C., J.W., W.S., X.Z., E.A., Y.L. and Z.G. analyzed the data; Z.C., J.W., A.R.K., J.B.B., F.S.L. and Z.G. wrote the paper.

Corresponding author

Correspondence to Zhen Gu.

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Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Table 1 and Supplementary Figures 1–34, Supplementary Note: Plasmid map and full plasmid sequence for glucose transporter 2 (GLUT2) (PDF 7430 kb)

Life Sciences Reporting Summary (PDF 1479 kb)

A movie showing the liposomes-in-liposome superstructures.

The inner small liposomes were incorporated with lipids labelled with nitrobenzofuran and outer larger liposome was incorporated with lipids labeled with lissamine rhodamine B. It can be seen that the small particles were moving randomly by Brownian motion inside the large liposomes. (MOV 200 kb)

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Chen, Z., Wang, J., Sun, W. et al. Synthetic beta cells for fusion-mediated dynamic insulin secretion. Nat Chem Biol 14, 86–93 (2018). https://doi.org/10.1038/nchembio.2511

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