The oral delivery of bioactive peptides and proteins is prevented by the intestinal epithelial barrier, in which intercellular tight junction complexes block the uptake of macromolecules. Here we show that anionic nanoparticles induce tight junction relaxation, increasing intestinal permeability and enabling the oral delivery of proteins. This permeation-enhancing effect is a function of nanoparticle size and charge, with smaller (≤ 200 nm) and more negative particles (such as silica) conferring enhanced permeability. In healthy mice, silica nanoparticles enabled the oral delivery of insulin and exenatide, with 10 U kg−1 orally delivered insulin sustaining hypoglycaemia for a few hours longer than a 1 U kg−1 dose of subcutaneously injected insulin. In healthy, hyperglycaemic and diabetic mice, the oral delivery of 10 U kg−1 insulin led to a dose-adjusted bioactivity of, respectively, 35%, 29% and 23% that of the subcutaneous injection of 1 U kg−1 insulin. The permeation-enhancing effect of the nanoparticles was reversible, non-toxic, and attributable to the binding to integrins on the surface of epithelial cells.
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The main data supporting the results in this study are available within the Article and Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request.
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The authors thank L. Kasiewicz for her assistance in revising and editing this manuscript. They also acknowledge M. Koval (Emory University) for his guidance on examining tight junctions. N.G.L. acknowledges funding support from the Thomas and Adrienne Klopack Graduate Fellowship and National Science Foundation Graduate Research Fellowship Program (NSF GRFP). This material is based on work supported by the NSF GRFP under grant no. DGE1252522. Any opinions, findings and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the NSF. The authors also acknowledge support from the National Institutes of Health, grant no. 1DP2OD026005-01.
K.A.W. and N.G.L. are registered as inventors on Patent Cooperation Treaty (PCT) application PCT/US2018/042035, which covers aspects of the technology presented here.
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Lamson, N.G., Berger, A., Fein, K.C. et al. Anionic nanoparticles enable the oral delivery of proteins by enhancing intestinal permeability. Nat Biomed Eng 4, 84–96 (2020). https://doi.org/10.1038/s41551-019-0465-5