A Granzyme B-Cleavable T Cell-Targeted Bispecific Cell Vesicle Connector for Reversing New-Onset Type 1 Diabetes

  • J Am Chem Soc. 2025 Feb 5;147(5):4167-4179. doi: 10.1021/jacs.4c13644.
Yanfang Wang  1 ,  Yanping Sun  1 ,  Xiuwen Zhang  1 ,  Shenqiang Wang  1 ,  Xuehui Huang  1  2 ,  Kairui Xu  1 ,  Yun Liu  1 ,  Yingqi Huang  1 ,  Jianchang Xu  1 ,  Xinwei Wei  1  2 ,  Hao Cheng  3 ,  Liqiang Pan  1 ,  Jinqiang Wang  1  2  4  5 ,  Zhen Gu  1  2  4  6  7  8  9
Affiliations
  • 1. State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2. Jinhua Institute of Zhejiang University, Jinhua 321299, China.
  • 3. Department of Materials Science and Engineering, Drexel University, Philadelphia, Pennsylvania 19104, United States.
  • 4. Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 5. Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
  • 6. Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
  • 7. Liangzhu Laboratory, Hangzhou 311121, China.
  • 8. Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou 310058, China.
  • 9. MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China.
PMID: 39869523 DOI: 10.1021/jacs.4c13644
Abstract

Type 1 diabetes (T1D) is an autoimmune disorder in which pancreatic β-cells are destroyed by CD8+ T cells. Anti-CD3 antibody effectively treats early-stage T1D when β-cell autoantibodies are detected but before symptoms appear. However, it impairs the immune system temporarily, exposing individuals to Infection. A therapeutic that can reverse new-onset T1D without harming the immune system remains urgently needed. Herein, we have constructed cellular vesicles presenting granzyme B-responsive fusion proteins (designated aCD8-GrzBcs-IL2) composed of a single-chain variable fragment of anti-CD8 antibodies and a mutein interleukin-2 (IL2). aCD8-GrzBcs-IL2 is designed to simultaneously inhibit CD8+ T cells and promote Treg cells, especially when CD8+ T cells are attacking β-cells. In vitro, these cellular vesicles can inhibit the cell-killing effect of CD8+ T cells and enhance the expansion of Treg cells. Notably, intravenous administration of aCD8-GrzBcs-IL2-expressed cellular vesicles reversed newly onset diabetes in 77.8% of nonobese diabetic (NOD) mice without reducing blood CD3+ T cells and CD8+ T cells, indicating a favorable safety profile.

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