Nanotargeted Delivery of Immune Therapeutics in Type 1 Diabetes

Sungwook Jung; Moufida Ben Nasr; Baharak Bahmani; Vera Usuelli; Jing Zhao; Gianmarco Sabiu; Andy Joe Seelam; Said Movahedi Naini; Hari Baskar Balasubramanian; Youngrong Park; Xiaofei Li; Salma Ayman Khalefa; Vivek Kasinath; MacKenzie D Williams; Ousama Rachid; Yousef Haik; George C Tsokos; Clive H Wasserfall; Mark A Atkinson; Jonathan S Bromberg; Wei Tao; Paolo Fiorina; Reza Abdi

doi:10.1002/adma.202300812

Nanotargeted Delivery of Immune Therapeutics in Type 1 Diabetes

Adv Mater. 2023 Oct;35(40):e2300812. doi: 10.1002/adma.202300812. Epub 2023 Aug 16.

Authors

Sungwook Jung¹, Moufida Ben Nasr^{2

3}, Baharak Bahmani¹, Vera Usuelli³, Jing Zhao¹, Gianmarco Sabiu¹, Andy Joe Seelam¹, Said Movahedi Naini¹, Hari Baskar Balasubramanian³, Youngrong Park¹, Xiaofei Li¹, Salma Ayman Khalefa³, Vivek Kasinath¹, MacKenzie D Williams⁴, Ousama Rachid⁵, Yousef Haik⁶, George C Tsokos⁷, Clive H Wasserfall⁴, Mark A Atkinson^{4

8}, Jonathan S Bromberg⁹, Wei Tao¹⁰, Paolo Fiorina^{1

2

3

11}, Reza Abdi¹

Affiliations

¹ Transplantation Research Center and Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
² Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
³ International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, 20157, Milan, Italy.
⁴ Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, 2713, Doha, Qatar.
⁶ Department of Mechanical and Nuclear Engineering, University of Sharjah, 27272, Sharjah, UAE.
⁷ Division of Rheumatology and Clinical Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.
⁸ Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA.
⁹ Departments of Surgery and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
¹⁰ Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
¹¹ Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy.

Abstract

Immune therapeutics holds great promise in the treatment of type 1 diabetes (T1D). Nonetheless, their progress is hampered by limited efficacy, equipoise, or issues of safety. To address this, a novel and specific nanodelivery platform for T1D that targets high endothelial venules (HEVs) presented in the pancreatic lymph nodes (PLNs) and pancreas is developed. Data indicate that the pancreata of nonobese diabetic (NOD) mice and patients with T1D are unique in their expression of newly formed HEVs. Anti-CD3 mAb is encapsulated in poly(lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles (NPs), the surfaces of which are conjugated with MECA79 mAb that recognizes HEVs. Targeted delivery of these NPs improves accumulation of anti-CD3 mAb in both the PLNs and pancreata of NOD mice. Treatment of hyperglycemic NOD mice with MECA79-anti-CD3-NPs results in significant reversal of T1D compared to those that are untreated, treated with empty NPs, or provided free anti-CD3. This effect is associated with a significant reduction of T effector cell populations in the PLNs and a decreased production of pro-inflammatory cytokine in the mice treated with MECA79-anti-CD3-NPs. In summary, HEV-targeted therapeutics may be used as a means by which immune therapeutics can be delivered to PLNs and pancreata to suppress autoimmune diabetes effectively.

Keywords: drug delivery; high endothelial venules; nanomedicine; targeted therapy; type 1 diabetes.

MeSH terms

Animals
Diabetes Mellitus, Type 1* / drug therapy
Humans
Mice
Mice, Inbred NOD
Pancreas

Abstract

MeSH terms

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