Anti-TNF-α antisense-oligonucleotide-conjugated PLG nanoparticles protect transplanted islets
One of the many challenges for islet transplantation as a treatment for type 1 diabetes is inflammation that contributes to islet de-differentiation and death. Innate immune cells such as monocytes and macrophages secrete tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), inducible nitric...
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| Language: | English |
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Elsevier
2025-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050125000841 |
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| author | Elizabeth J. Bealer Namit Padgaonkar Kelly Crumley Eiji Saito Zoe Beekman Alexa DeKorte Thazha P. Prakash Alexey Revenko Lonnie D. Shea |
| author_facet | Elizabeth J. Bealer Namit Padgaonkar Kelly Crumley Eiji Saito Zoe Beekman Alexa DeKorte Thazha P. Prakash Alexey Revenko Lonnie D. Shea |
| author_sort | Elizabeth J. Bealer |
| collection | DOAJ |
| description | One of the many challenges for islet transplantation as a treatment for type 1 diabetes is inflammation that contributes to islet de-differentiation and death. Innate immune cells such as monocytes and macrophages secrete tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), inducible nitric oxide synthase (iNOS), and IL-6, which directly contribute to islet dysfunction. Attenuation of the early inflammatory response post-transplantation may protect cell survival and subsequent function. Herein, we investigate the development of anti-TNF-α antisense-oligonucleotide-conjugated polylactide-co-glycolide nanoparticles (PLG-aTNF-α NPs) as an anti-inflammatory therapy after stem-cell-derived islet transplantation. PLG-aTNF-α NPs are shelf stable and successfully reduce TNF-α secretion and expression in inflammatory macrophages. Synergy between the aTNF-α antisense oligonucleotide and the polylactide-co-glycolide NPs results in further knockdown of IL-1β, IL-6, iNOS, and IL-12 in vitro indicating PLG-aTNF-α NPs may protect against the inflammatory cascade in vivo. In a diabetic mouse model, stem-cell-derived islets transplanted to the peritoneal fat were protected after treatment with PLG-aTNF-α NPs compared with PLG NPs alone. Tnfα and Il1β expression was reduced in mice treated with PLG-aTNF-α NPs, indicating inflammation was reduced after transplant. PLG-aTNF-α NPs reduce TNF-α and protect islets, supporting their potential use as a therapeutic in islet transplantation. |
| format | Article |
| id | doaj-art-9f131def41a44e4caf6ca3969f6ca5fc |
| institution | DOAJ |
| issn | 2329-0501 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-9f131def41a44e4caf6ca3969f6ca5fc2025-08-20T03:08:21ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012025-06-0133210148910.1016/j.omtm.2025.101489Anti-TNF-α antisense-oligonucleotide-conjugated PLG nanoparticles protect transplanted isletsElizabeth J. Bealer0Namit Padgaonkar1Kelly Crumley2Eiji Saito3Zoe Beekman4Alexa DeKorte5Thazha P. Prakash6Alexey Revenko7Lonnie D. Shea8Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USADepartment of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USADepartment of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USADepartment of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USADepartment of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USADepartment of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USAIONIS Pharmaceuticals, Carlsbad, CA, USAIONIS Pharmaceuticals, Carlsbad, CA, USADepartment of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USA; Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author: Lonnie D. Shea, Department of Biomedical Engineering, University of Michigan, 1600 Huron Parkway NCRC Bldg 520, Ann Arbor, MI 48109, USA.One of the many challenges for islet transplantation as a treatment for type 1 diabetes is inflammation that contributes to islet de-differentiation and death. Innate immune cells such as monocytes and macrophages secrete tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), inducible nitric oxide synthase (iNOS), and IL-6, which directly contribute to islet dysfunction. Attenuation of the early inflammatory response post-transplantation may protect cell survival and subsequent function. Herein, we investigate the development of anti-TNF-α antisense-oligonucleotide-conjugated polylactide-co-glycolide nanoparticles (PLG-aTNF-α NPs) as an anti-inflammatory therapy after stem-cell-derived islet transplantation. PLG-aTNF-α NPs are shelf stable and successfully reduce TNF-α secretion and expression in inflammatory macrophages. Synergy between the aTNF-α antisense oligonucleotide and the polylactide-co-glycolide NPs results in further knockdown of IL-1β, IL-6, iNOS, and IL-12 in vitro indicating PLG-aTNF-α NPs may protect against the inflammatory cascade in vivo. In a diabetic mouse model, stem-cell-derived islets transplanted to the peritoneal fat were protected after treatment with PLG-aTNF-α NPs compared with PLG NPs alone. Tnfα and Il1β expression was reduced in mice treated with PLG-aTNF-α NPs, indicating inflammation was reduced after transplant. PLG-aTNF-α NPs reduce TNF-α and protect islets, supporting their potential use as a therapeutic in islet transplantation.http://www.sciencedirect.com/science/article/pii/S2329050125000841antisense oligonucleotideTNF-αSC isletsinflammationcell transplant |
| spellingShingle | Elizabeth J. Bealer Namit Padgaonkar Kelly Crumley Eiji Saito Zoe Beekman Alexa DeKorte Thazha P. Prakash Alexey Revenko Lonnie D. Shea Anti-TNF-α antisense-oligonucleotide-conjugated PLG nanoparticles protect transplanted islets Molecular Therapy: Methods & Clinical Development antisense oligonucleotide TNF-α SC islets inflammation cell transplant |
| title | Anti-TNF-α antisense-oligonucleotide-conjugated PLG nanoparticles protect transplanted islets |
| title_full | Anti-TNF-α antisense-oligonucleotide-conjugated PLG nanoparticles protect transplanted islets |
| title_fullStr | Anti-TNF-α antisense-oligonucleotide-conjugated PLG nanoparticles protect transplanted islets |
| title_full_unstemmed | Anti-TNF-α antisense-oligonucleotide-conjugated PLG nanoparticles protect transplanted islets |
| title_short | Anti-TNF-α antisense-oligonucleotide-conjugated PLG nanoparticles protect transplanted islets |
| title_sort | anti tnf α antisense oligonucleotide conjugated plg nanoparticles protect transplanted islets |
| topic | antisense oligonucleotide TNF-α SC islets inflammation cell transplant |
| url | http://www.sciencedirect.com/science/article/pii/S2329050125000841 |
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