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  • Review Article
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Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead

Nature Reviews Endocrinology volume 21, pages 14–30 (2025)Cite this article

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Abstract

Type 1 diabetes mellitus (T1DM) is a growing global health concern that affects approximately 8.5 million individuals worldwide. T1DM is characterized by an autoimmune destruction of pancreatic β cells, leading to a disruption in glucose homeostasis. Therapeutic intervention for T1DM requires a complex regimen of glycaemic monitoring and the administration of exogenous insulin to regulate blood glucose levels. Advances in continuous glucose monitoring and algorithm-driven insulin delivery devices have improved the quality of life of patients. Despite this, mimicking islet function and complex physiological feedback remains challenging. Pancreatic islet transplantation represents a potential functional cure for T1DM but is hindered by donor scarcity, variability in harvested cells, aggressive immunosuppressive regimens and suboptimal clinical outcomes. Current research is directed towards generating alternative cell sources, improving transplantation methods, and enhancing cell survival without chronic immunosuppression. This Review maps the progress in cell replacement therapies for T1DM and outlines the remaining challenges and future directions. We explore the state-of-the-art strategies for generating replenishable β cells, cell delivery technologies and local targeted immune modulation. Finally, we highlight relevant animal models and the regulatory aspects for advancing these technologies towards clinical deployment.

Key points

  • Stem cell-derived islets have advanced as a viable renewable source of cells for transplantation in type 1 diabetes mellitus (T1DM). Although these cells are being tested in the clinical setting, challenges remain to be addressed regarding cell safety, composition and function.

  • Genetic engineering of renewable β cells can reduce immunogenicity, lower metabolic needs and bolster hypoxia resistance. However, the effect on β cell performance requires further elucidation.

  • Local immunomodulation via in situ delivery of immunomodulatory molecules and adjuvant cells is emerging as a promising approach for abrogating the need for systemic immunosuppression in β cell transplantation.

  • Current preclinical results suggest that immunoprotected islet cell grafts in a retrievable subcutaneous site could restore normoglycaemia for at least 1 year or longer without systemic immunosuppression.

  • Despite the potential of new technologies, the development of cell therapy treatments must pragmatically focus on generating therapies that are not only effective and safe but also align with the real-world dynamics of patients’ lives and the capabilities of health-care systems.

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Fig. 1: Pluripotent stem cell differentiation into stem cell-derived islets through modulation of different genes.
Fig. 2: Microencapsulation approaches for islet transplantation.
Fig. 3: Direct vascularization scaffolds and open devices.

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Acknowledgements

A.G. is supported by NIH NIDDK R01DK132104, R01DK133610, JDRF 2-SRA-2022-1224-S-B, JDRF 2-SRA-2021-1078-S-B, Vivian Smith Foundation and Men of Distinction. A.R.P. is supported through a JDRF Career Development Award (5-CDA-2020-945-A-N) and is a Canada Research Chair in Cell Therapies for Diabetes thanks to funding from the Canada Research Chairs Program. A.C. is supported by a grant from JDRF (3-SRA-2022-1155-S-B) and the Italian Ministry of Health (GR-2018-12366399). M.B. is a consultant for The Jackson Laboratory. J.R.M. was supported by the NIH (R01DK114233), JDRF (3-SRA-2023-1295-S-B), and the Edward J Mallinckrodt Foundation. H.A.R. is or was supported by NIDDK R01DK12044, NIDDK R01DK132387, NINDS 1R01NS122911, NIDDK/HIRN RRID: SCR_014393; UC24 DK104162, JDRF SRA 2-SRA-2023-1313-S-B and 3-SRA-2023-1367-S-B, and the Diabetes Research Connection. M.C.P. is supported by JDRF grants 2-SRA 2021 1075-S-B and 3-SRA 2023 1365-S-B, the VIC Innovation Fund and The Hill Family Foundation. F. Dogan helped to create Fig. 2. The authors thank S. P. Rodgers and R. E. Whitehead for their support in finalizing the manuscript and figures.

Author information

Author notes

  1. These authors contributed equally: Nicholas E. Mamrak, Jaime Giraldo, Mark C. Poznansky, Paul de Vos.

Authors and Affiliations

  1. Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA

    Alessandro Grattoni

  2. Department of Surgery, Houston Methodist Hospital, Houston, TX, USA

    Alessandro Grattoni

  3. Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX, USA

    Alessandro Grattoni

  4. Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada

    Gregory Korbutt

  5. Department of Surgery, University of Alberta, Edmonton, Alberta, Canada

    Gregory Korbutt & Andrew R. Pepper

  6. Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA

    Alice A. Tomei, Norma Kenyon & Camillo Ricordi

  7. Department of Biomedical Engineering, University of Miami, Miami, FL, USA

    Alice A. Tomei

  8. Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Alice A. Tomei, Norma Kenyon & Camillo Ricordi

  9. Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA

    Alice A. Tomei

  10. Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA

    Andrés J. García

  11. J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL, USA

    Cherie Stabler

  12. Diabetes Institute, University of Florida, Gainesville, FL, USA

    Cherie Stabler & Holger A. Russ

  13. Program in Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, USA

    Michael Brehm

  14. Department of Surgery, The University of Arizona, Tucson, AZ, USA

    Klearchos Papas

  15. Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy

    Antonio Citro

  16. Department of Pediatrics, Ellis Fischel Cancer Center, School of Medicine, University of Missouri, Columbia, MO, USA

    Haval Shirwan

  17. Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA

    Jeffrey R. Millman

  18. Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA

    Jeffrey R. Millman

  19. Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA, USA

    Juan Melero-Martin

  20. Department of Surgery, Harvard Medical School, Boston, MA, USA

    Juan Melero-Martin

  21. Harvard Stem Cell Institute, Cambridge, MA, USA

    Juan Melero-Martin

  22. Department of Surgery, University of Minnesota, Minneapolis, MN, USA

    Melanie Graham

  23. Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, USA

    Melanie Graham

  24. Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada

    Michael Sefton

  25. Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada

    Michael Sefton

  26. Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA

    Minglin Ma

  27. Department of Bioengineering, Rice University, Houston, TX, USA

    Omid Veiseh

  28. University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences, San Francisco, CA, USA

    Tejal A. Desai

  29. Brown University, School of Engineering, Providence, RI, USA

    Tejal A. Desai

  30. McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada

    M. Cristina Nostro

  31. Department of Physiology, University of Toronto, Toronto, ON, Canada

    M. Cristina Nostro

  32. Advocacy Department, Breakthrough T1D, Washington, DC, USA

    Marjana Marinac

  33. Department of Medicine, Columbia Center for Translational Immunology, Columbia University, New York, NY, USA

    Megan Sykes

  34. Department of Microbiology and Immunology, Columbia University, New York, NY, USA

    Megan Sykes

  35. Department of Surgery, Columbia University, New York, NY, USA

    Megan Sykes

  36. Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA

    Holger A. Russ

  37. UW Health Transplant Center, Madison, WI, USA

    Jon Odorico

  38. Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Jon Odorico

  39. Diabetes Center, University of California San Francisco, San Francisco, CA, USA

    Qizhi Tang

  40. Department of Surgery, University of California San Francisco, San Francisco, CA, US

    Qizhi Tang

  41. Gladstone Institute of Genomic Immunology, University of California San Francisco, San Francisco, CA, USA

    Qizhi Tang

  42. Research Department, Breakthrough T1D, New York, NY, USA

    Esther Latres, Nicholas E. Mamrak & Jaime Giraldo

  43. Vaccine and Immunotherapy Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Mark C. Poznansky

  44. Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands

    Paul de Vos

Authors
  1. Alessandro Grattoni
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  2. Gregory Korbutt
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Contributions

A.G., N.E.M., J.G., M.C.P. and P.deV. researched data for the article, made a substantial contribution to discussion of content, wrote, and reviewed/edited the manuscript before submission. G.K., A.A.T., A.J.G., A.R.P., C.S., M.B., K.P., A.C., H.S., J.R.M., J.M.-M., M.G., M. Sefton, M. Ma, N.K., O.V., T.A.D., M.C.N., M. Marinac, M. Sykes, H.A.R., J.O. and Q.T. researched data for the article, made a substantial contribution to discussion of content and wrote the article. C.R. and E.L. wrote, and reviewed/edited the manuscript before submission.

Corresponding authors

Correspondence to Alessandro Grattoni, Jaime Giraldo, Mark C. Poznansky or Paul de Vos.

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Competing interests

A.G. is a co-founder of Continuity Biosciences LLC, and an inventor of intellectual property licensed by the same company. A.J.G. is an inventor of intellectual property related to technologies for cell therapy in T1DM owned in part by the Georgia Tech Research Corporation, is a co-founder, sits on the Board of Directors, and owns equity interest in iTolerance Inc. H.S. is an inventor on a patent licensed by iTolerance Inc, is a co-founder of the Company, and serves on the scientific advisory board of the Company. M. Ma is a co-founder and equity holder of AvantGuard and Persista Bio. J.O. is co-founder, owns stock equity, and serves on the scientific advisory board of Regenerative Medical Solutions Inc., is a clinical trial investigator for Vertex Pharmaceuticals Inc., and is a member of DSMB for Sernova Corp. J.R.M. is an inventor on related patents and patent applications, was employed at Sana Biotechnology, and has stocks and options in Sana Biotechnology. T.A.D. is a scientific founder of Encellin Inc., a cell therapy device company. K.P. discloses interest in Procyon Technologies LLC. M.C.N. has a sponsored research agreement with Universal Cells Inc., and a patent licensed to Sernova Corp. H.A.R. holds patents in the regenerative medicine space and served as SAB member of Sigilon Therapeutics, Prellis Biologics and consults or consulted for Sigilon Therapeutics, Eli Lilly, Minutia, Guidepoint Global, Axon Advisors and Tolerance Bio. C.R. is scientific adviser to Novo Nordisk, Vertex Pharma and iTolerance, and is a founding scientist of Lipogems International and AION Healthspan. M.C.P. is scientific founder of Vicapsys Life Sciences Inc. All other authors declare no competing interests.

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Nature Reviews Endocrinology thanks Emmanuel Opara, Adrian Teo, Shareen Forbes for their contribution to the peer review of this work.

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Grattoni, A., Korbutt, G., Tomei, A.A. et al. Harnessing cellular therapeutics for type 1 diabetes mellitus: progress, challenges, and the road ahead. Nat Rev Endocrinol 21, 14–30 (2025). https://doi.org/10.1038/s41574-024-01029-0

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