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Supporting Information - proof revised 240527[AU].pdf (2 MB)

Bioengineered Artificial Extracellular Vesicles Presenting PD-L1 and Gal-9 Ameliorate New-onset Type 1 Diabetes

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Version 2 2024-05-28, 15:00
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posted on 2024-05-28, 15:00 authored by Zhaoxin Yang, Zhirang Zhang, Liyan Li, Zhangyan Jing, Yumeng Ma, Tianyu Lan, Yuan Li, Zhongda Lin, Wenli Fang, Jinxie Zhang, Jinling Zhang, Xin Liang, Benqing Wu, Yi Zheng, Xudong Zhang

An important factor in the development of Type 1 diabetes (T1D) is the deficiency of inhibitory immune checkpoint ligands, specifically programmed cell death ligand 1 (PD-L1) and Galectin-9 (Gal-9), in β-cells. Hence, modulation of the pancreas infiltrated T lymphocytes by exogenous PD-L1 or Gal-9 is an ideal approach for treating the new-onset T1D. Herein, we genetic engineered the macrophage cells to generate artificial extracellular vesicles (aEVs) overexpressing PD-L1 and Gal-9, which could restrict the islets auto-reactive T lymphocytes and protect β-cells from destruction. Intriguingly, overexpressing Gal-9 spurred macrophage polarization to M2 phenotype with immune suppressive attribute. Alternatively, both of PD-L1 and Gal-9 presenting aEVs (PD-L1-Gal-9 aEVs) favorably adhere to T cells via the interaction of programmed cell death protein 1 (PD-1)/PD-L1 or T cell immunoglobulin mucin 3 (TIM-3)/Gal-9. Moreover, PD-L1-Gal-9 aEVs prominently promoted effector T cell apoptosis and splenic regulatory T cells (Treg) cells differentiation in vitro. Virtually, PD-L1-Gal-9 aEVs efficaciously reversed the new-onset hyperglycemia in the NOD mice, prevented T1D progress, and declined the proportion and activation of CD4+ and CD8+ T cells infiltrating the pancreas notably, which together contributed to preserving the residual β-cells survival and mitigating the hyperglycemia.

Funding

This work was supported by grants from The National Natural Science Foundation of China (32371425,31971268, 32201084), Shenzhen Science and Technology Program (Grant No. RCYX20200714114643121), Science, Technology & Innovation Commission of Shenzhen Municipality (JCYJ20200109142610136, JCYJ20180507181654186, JCYJ20220530165407018, ZDSYS20220606100803007), Guangdong Basic and Applied Basic Research Foundation (2019A1515010855, 2020A1515110166), the Natural Science Foundation of Guangdong Province (No.2020A1515010802, No.2022A1515012289), University of Chinese Academy of Sciences-Shenzhen Hospital Research Funding (HRF-2020004), and the Health system scientific research project of Shenzhen Guangming District Science and innovation Bureau (2020R01073, 2020R01061), Special fund for economic development of ShenZhen Guangming District (2021R01128, 2021R01120), Doctoral personnel scientific research start-up Fund project of Guangdong Medical University (GDMUB2022037), and Shenzhen Guangming District Economic Development Special Fund (2021R01055).

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