Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin

Nature Biomedical Engineering volume 5, pages 983–997 (2021)Cite this article

Subjects

An Author Correction to this article was published on 04 November 2021

This article has been updated

Abstract

Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Bile-acid polymers formulated into drug-loaded biodegradable nanoparticles.
Fig. 2: Composition and dose-dependent pancreatic accumulation of pBA nanoparticles.
Fig. 3: Prevention of T1D.
Fig. 4: Short-term treatment and long-term regression of T1D after pUDCAIns nanoparticle oral ingestion, activation of TGR5-induced endogenous GLP-1 and insulin secretion, and anti-inflammatory effect of pUDCA.
Fig. 5: Increased stability in the stomach milieu, permeation through intestinal cells and pUDCA nanoparticle binding to TGR5 with high avidity.
Fig. 6: Mechanisms of pUDCA biodistribution, pancreatic accumulation and immune modulation after oral ingestion.

Similar content being viewed by others

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. Source data for the figures are provided with this paper. The raw and analysed datasets generated during the study are too large to be publicly shared, but are available for research purposes from the corresponding author on reasonable request.

Change history

References

  1. Chen, M. C., Sonaje, K., Chen, K. J. & Sung, H. W. A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery. Biomaterials 32, 9826–9838 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Iyer, H., Khedkar, A. & Verma, M. Oral insulin—a review of current status. Diabetes Obes. Metab. 12, 179–185 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Lowman, A. M., Morishita, M., Kajita, M., Nagai, T. & Peppas, N. A. Oral delivery of insulin using pH-responsive complexation gels. J. Pharm. Sci. 88, 933–937 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Mitragotri, S., Burke, P. A. & Langer, R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat. Rev. Drug Discov. 13, 655–672 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Goldberg, M. & Gomez-Orellana, I. Challenges for the oral delivery of macromolecules. Nat. Rev. Drug Discov. 2, 289–295 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Miron, N. & Cristea, V. Enterocytes: active cells in tolerance to food and microbial antigens in the gut. Clin. Exp. Immunol. 167, 405–412 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Riddle, M. C. Evening insulin strategy. Diabetes Care 13, 676–686 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Buschard, K. The functional state of the beta cells in the pathogenesis of insulin-dependent diabetes mellitus. Autoimmunity 10, 65–69 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Argoud, G. M., Schade, D. S. & Eaton, R. P. Insulin suppresses its own secretion in vivo. Diabetes 36, 959–962 (1987).

    Article  CAS  PubMed  Google Scholar 

  10. Palmer, J. P. et al. Interaction of beta-cell activity and IL-1 concentration and exposure time in isolated rat islets of Langerhans. Diabetes 38, 1211–1216 (1989).

    Article  CAS  PubMed  Google Scholar 

  11. Johansen, N. J. & Christensen, M. B. A systematic review on insulin overdose cases: clinical course, complications and treatment options. Basic Clin. Pharmacol. Toxicol. 122, 650–659 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Hanas, R. & Ludvigsson, J. Hypoglycemia and ketoacidosis with insulin pump therapy in children and adolescents. Pediatr. Diabetes 7, 32–38 (2006).

    Article  PubMed  Google Scholar 

  13. Mathieu, C., Gillard, P. & Benhalima, K. Insulin analogues in type 1 diabetes mellitus: getting better all the time. Nat. Rev. Endocrinol. 13, 385–399 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Fawcett, J., Hamel, F. G., Bennett, R. G., Vajo, Z. & Duckworth, W. C. Insulin and analogue effects on protein degradation in different cell types. Dissociation between binding and activity. J. Biol. Chem. 276, 11552–11558 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Park, K., Kwon, I. C. & Park, K. Oral protein delivery: current status and future prospect. React. Funct. Polym. 71, 280–287 (2011).

    Article  CAS  Google Scholar 

  16. Sadekar, S. & Ghandehari, H. Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery. Adv. Drug Deliv. Rev. 64, 571–588 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Sweet, D. M., Kolhatkar, R. B., Ray, A., Swaan, P. & Ghandehari, H. Transepithelial transport of PEGylated anionic poly(amidoamine) dendrimers: implications for oral drug delivery. J. Control. Release 138, 78–85 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang, Z., Li, H., Xu, G. & Yao, P. Liver-targeted delivery of insulin-loaded nanoparticles via enterohepatic circulation of bile acids. Drug Deliv. 25, 1224–1233 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ahmad, N., Mohd Amin, M. C., Ismail, I. & Buang, F. Enhancement of oral insulin bioavailability: in vitro and in vivo assessment of nanoporous stimuli-responsive hydrogel microparticles. Expert Opin. Drug Deliv. 13, 621–632 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Abramson, A. et al. An ingestible self-orienting system for oral delivery of macromolecules. Science 363, 611–615 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mooranian, A., Negrulj, R., Arfuso, F. & Al-Salami, H. Characterization of a novel bile acid-based delivery platform for microencapsulated pancreatic beta-cells. Artif. Cells Nanomed. Biotechnol. 44, 194–200 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Al-Salami, H., Butt, G., Tucker, I. & Mikov, M. Influence of the semisynthetic bile acid MKC on the ileal permeation of gliclazide in vitro in healthy and diabetic rats treated with probiotics. Methods Find. Exp. Clin. Pharmacol. 30, 107–113 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Biagioli, M. et al. The bile acid receptor GPBAR1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from murine colitis. J. Immunol. 199, 718–733 (2017).

    Article  CAS  PubMed  Google Scholar 

  24. Brighton, C. A. et al. Bile acids trigger GLP-1 release predominantly by accessing basolaterally located G protein-coupled bile acid receptors. Endocrinology 156, 3961–3970 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chavez-Talavera, O., Tailleux, A., Lefebvre, P. & Staels, B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 152, 1679–1683 (2017).

    Article  CAS  PubMed  Google Scholar 

  26. Chiang, J. Y. Bile acid metabolism and signaling. Compr. Physiol. 3, 1191–1212 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Mathavan, S., Chen-Tan, N., Arfuso, F. & Al-Salami, H. The role of the bile acid chenodeoxycholic acid in the targeted oral delivery of the anti-diabetic drug gliclazide, and its applications in type 1 diabetes. Artif. Cells Nanomed. Biotechnol. 44, 1508–1519 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Chung, Y. R., Choi, J. A., Koh, J. Y. & Yoon, Y. H. Ursodeoxycholic acid attenuates endoplasmic reticulum stress-related retinal pericyte loss in streptozotocin-induced diabetic mice. J. Diabetes Res. 2017, 1763292 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Cao, A. L. et al. Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy. Lab Invest. 96, 610–622 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167–177 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Duboc, H., Tache, Y. & Hofmann, A. F. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig. Liver Dis. 46, 302–312 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Katsuma, S., Hirasawa, A. & Tsujimoto, G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem. Biophys. Res. Commun. 329, 386–390 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Ibrahim, E. et al. Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: role of Gi protein, muscarinic receptors and TGR5. Sci. Rep. 8, 7110 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Iguchi, Y. et al. Effects of chemical modification of ursodeoxycholic acid on TGR5 activation. Biol. Pharm. Bull. 34, 1–7 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Malisova, L. et al. Ursodeoxycholic acid but not tauroursodeoxycholic acid inhibits proliferation and differentiation of human subcutaneous adipocytes. PLoS ONE 8, e82086 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Samstein, R. M., Perica, K., Balderrama, F., Look, M. & Fahmy, T. M. The use of deoxycholic acid to enhance the oral bioavailability of biodegradable nanoparticles. Biomaterials 29, 703–708 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Westergaard, H. & Dietschy, J. M. The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell. J. Clin. Invest. 58, 97–108 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Stringer, M. D. Eponyms in Surgery and Anatomy of the Liver, Bile Ducts and Pancreas 1st edn (RSM Press, 2009).

  39. Fan, W. W. et al. Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery. Biomaterials 151, 13–23 (2018).

    Article  CAS  PubMed  Google Scholar 

  40. Zuluaga, F., Valderruten, N. E. & Wagener, K. B. The ambient temperature synthesis and characterization of bile acid polymers. Polym. Bull. 42, 41–46 (1999).

    Article  CAS  Google Scholar 

  41. Iqbal, M., Zafar, N., Fessi, H. & Elaissari, A. Double emulsion solvent evaporation techniques used for drug encapsulation. Int. J. Pharm. 496, 173–190 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, T. Y., Liu, M., Portincasa, P. & Wang, D. Q. H. New insights into the molecular mechanism of intestinal fatty acid absorption. Eur. J. Clin. Invest. 43, 1203–1223 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Faustino, C., Serafim, C., Rijo, P. & Reis, C. P. Bile acids and bile acid derivatives: use in drug delivery systems and as therapeutic agents. Expert Opin. Drug Deliv. 13, 1133–1148 (2016).

    Article  CAS  PubMed  Google Scholar 

  44. Aburahma, M. H. Bile salts-containing vesicles: promising pharmaceutical carriers for oral delivery of poorly water-soluble drugs and peptide/protein-based therapeutics or vaccines. Drug Deliv. 23, 1847–1867 (2016).

    CAS  PubMed  Google Scholar 

  45. Chen, Y. P. et al. Enhanced bioavailability of the poorly water-soluble drug fenofibrate by using liposomes containing a bile salt. Int. J. Pharm. 376, 153–160 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Song, K. H., Chung, S. J. & Shim, C. K. Enhanced intestinal absorption of salmon calcitonin (sCT) from proliposomes containing bile salts. J. Control. Release 106, 298–308 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Kim, S. K. et al. Evaluation of absorption of heparin-DOCA conjugates on the intestinal wall using a surface plasmon resonance. J. Pharm. Biomed. Anal. 39, 861–870 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Allen, K., Jaeschke, H. & Copple, B. L. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am. J. Pathol. 178, 175–186 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hamad, A. R. et al. Potent T cell activation with dimeric peptide–major histocompatibility complex class II ligand: the role of CD4 coreceptor. J. Exp. Med. 188, 1633–1640 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fahmy, T. M., Schneck, J. P. & Saltzman, W. M. A nanoscopic multivalent antigen-presenting carrier for sensitive detection and drug delivery to T cells. Nanomedicine 3, 75–85 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Waldner, M., Fantus, D., Solari, M. & Thomson, A. W. New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation. Br. J. Clin. Pharmacol. 82, 1158–1170 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Delovitch, T. L. & Singh, B. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7, 727–738 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Lundberg, R. L. et al. Partial clinical remission in type 1 diabetes: a comparison of the accuracy of total daily dose of insulin of <0.3 units/kg/day to the gold standard insulin-dose adjusted hemoglobin A1c of </=9 for the detection of partial clinical remission. J. Pediatr. Endocrinol. Metab. 30, 823–830 (2017).

    Article  CAS  PubMed  Google Scholar 

  54. Labowsky, M. & Fahmy, T. M. Diffusive transfer between two intensely interacting cells with limited surface kinetics. Chem. Eng. Sci. 74, 114–123 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Steenblock, E. R., Fadel, T., Labowsky, M., Pober, J. S. & Fahmy, T. M. An artificial antigen-presenting cell with paracrine delivery of IL-2 impacts the magnitude and direction of the T cell response. J. Biol. Chem. 286, 34883–34892 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Labowsky, M., Lowenthal, J. & Fahmy, T. M. An in silico analysis of nanoparticle/cell diffusive transfer: application to nano-artificial antigen-presenting cell:T-cell interaction. Nanomedicine 11, 1019–1028 (2015).

  57. Badin, J. K. et al. Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome. J. Transl. Med. 16, PMC5845376 (2018).

    Article  CAS  Google Scholar 

  58. Hofmann, A. F. & Mysels, K. J. Bile acid solubility and precipitation in vitro and in vivo: the role of conjugation, pH, and Ca2+ ions. J. Lipid Res. 33, 617–626 (1992).

    Article  CAS  PubMed  Google Scholar 

  59. Thakral, S., Thakral, N. K. & Majumdar, D. K. Eudragit: a technology evaluation. Expert Opin. Drug Deliv. 10, 131–149 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Zolnik, B. S. & Burgess, D. J. Effect of acidic pH on PLGA microsphere degradation and release. J. Control. Release 122, 338–344 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Dawson, P. A. & Karpen, S. J. Intestinal transport and metabolism of bile acids. J. Lipid Res. 56, 1085–1099 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gao, Y. et al. Modulation of intestinal epithelial permeability in differentiated Caco-2 cells exposed to aflatoxin M1 and ochratoxin A individually or collectively. Toxins 10, PMC5793100 (2017).

    Article  CAS  Google Scholar 

  63. Artursson, P. & Karlsson, J. Correlation between oral-drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. Res. Commun. 175, 880–885 (1991).

    Article  CAS  PubMed  Google Scholar 

  64. Bain, C. C. & Mowat, A. M. Macrophages in intestinal homeostasis and inflammation. Immunol. Rev. 260, 102–117 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. van Rooijen, N. & Hendrikx, E. Liposomes for specific depletion of macrophages from organs and tissues. Methods Mol. Biol. 605, 189–203 (2010).

    Article  PubMed  CAS  Google Scholar 

  66. Kim, K. S., Suzuki, K., Cho, H., Youn, Y. S. & Bae, Y. H. Oral nanoparticles exhibit specific high-efficiency intestinal uptake and lymphatic transport. ACS Nano 12, 8893–8900 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ceryak, S., Bouscarel, B. & Fromm, H. Comparative binding of bile-acids to serum-lipoproteins and albumin. J. Lipid Res. 34, 1661–1674 (1993).

    Article  CAS  PubMed  Google Scholar 

  68. Essell, J. H. et al. Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 128, 975–981 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Kumar, D. P. et al. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic beta cells. Biochem. Biophys. Res. Commun. 427, 600–605 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Shima, K. R. et al. Ursodeoxycholic acid potentiates dipeptidyl peptidase-4 inhibitor sitagliptin by enhancing glucagon-like peptide-1 secretion in patients with type 2 diabetes and chronic liver disease: a pilot randomized controlled and add-on study. BMJ Open Diabetes Res. Care 6, e000469 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Kramer, R. H. & Karpen, J. W. Spanning binding sites on allosteric proteins with polymer-linked ligand dimers. Nature 395, 710–713 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Ragheb, R. R. et al. Induced clustered nanoconfinement of superparamagnetic iron oxide in biodegradable nanoparticles enhances transverse relaxivity for targeted theranostics. Magn. Reson. Med. 70, 1748–1760 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Kowapradit, J. et al. In vitro permeability enhancement in intestinal epithelial cells (Caco-2) monolayer of water soluble quaternary ammonium chitosan derivatives. AAPS PharmSciTech 11, 497–508 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Park, J. et al. Enhancement of surface ligand display on PLGA nanoparticles with amphiphilic ligand conjugates. J. Control. Release 156, 109–115 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Brode, S., Raine, T., Zaccone, P. & Cooke, A. Cyclophosphamide-induced type-1 diabetes in the NOD mouse is associated with a reduction of CD4+CD25+Foxp3+ regulatory T cells. J. Immunol. 177, 6603–6612 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Look, M. et al. Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice. J. Clin. Invest. 123, 1741–1749 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank K. Herold and R. Flavell for helpful discussions and input regarding the diabetic animal models and future applications of the technology; Pfizer Autoimmune Inc. (Cambridge, MA) for partial funding of this work; the JDRF for an early pilot grant that motivated the work; the Yale Autoimmune Center of Excellence pilot grant to T.M.F. (director K. Herold). This work was partially supported by NIH grants 1R01CA199004 and 1R01CA026412 to T.M.F and Toralgen Inc., by Novartis Institutes for BioMedical Research and by the Yale Institute for Nanoscience and Quantum Engineering to T.M.F.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Yale University, New Haven, CT, USA

    Jung Seok Lee, Shihan Khan, Sean Bickerton, Michael D. McHugh, Alyssa L. Siefert, Jason Criscione, Karlo Perica, Robert Samstein, Ragy Ragheb, Dongin Kim & Tarek M. Fahmy

  2. Chemical and Environmental Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA

    Patrick Han, Rabib Chaudhury & Tarek M. Fahmy

  3. Department of Chemistry, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA

    Hyun Bong Park

  4. Toralgen Inc., Indianapolis, IN, USA

    Gerald Rea

  5. Novartis Institutes for BioMedical Research, Basel, Switzerland

    José M. Carballido

  6. Medicine and Molecular Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    David A. Horwitz

  7. Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Dongin Kim

  8. Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA

    Tarek M. Fahmy

Authors
  1. Jung Seok Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rabib Chaudhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shihan Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sean Bickerton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael D. McHugh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hyun Bong Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alyssa L. Siefert
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gerald Rea
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. José M. Carballido
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. David A. Horwitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jason Criscione
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Karlo Perica
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Robert Samstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ragy Ragheb
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Dongin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Tarek M. Fahmy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.S.L. performed most experiments, wrote the methods and edited the manuscript. D.K. helped with the in vivo experiments. P.H. and R.C. assisted with animal experiments. P.H., R.C., S.K., S.B. and M.D.M. helped with flow cytometry, ELISA and data analysis. H.B.P. performed NMR and analysed spectra. G.R. contributed to the pig experiments. J.M.C. and A.L.S. were involved in the experimental design and provided intellectual feedback. D.A.H. provided gifts that partially supported this work and intellectual feedback. K.P., R.S., J.C. and R.R. were involved in the initial design and in vitro testing of the polymer. T.M.F. supervised the project, conceptualized and designed all experiments and prepared the manuscript.

Corresponding author

Correspondence to Tarek M. Fahmy.

Ethics declarations

Competing interests

T.M.F is a founder and major shareholder of Toralgen Inc., which focuses on the use of the system described in this work for different disease states, including autoimmunity and specifically type 1 and type 2 diabetes.

Additional information

Peer review information Nature Biomedical Engineering thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary figures and tables.

Reporting Summary

Supplementary Data

Data used to make the graphs in Figs. 2–4 and Supplementary Figs. 3–9.

Peer Review File

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, J.S., Han, P., Chaudhury, R. et al. Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin. Nat Biomed Eng 5, 983–997 (2021). https://doi.org/10.1038/s41551-021-00791-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-021-00791-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research