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

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. Therefore, modulation of pancreas-infiltrated T lymphocytes by exogenous PD-L1 or Gal-9 is an ideal approach for treating new-onset T1D. We genetically engineered macrophage cells to generate artificial extracellular vesicles (aEVs) overexpressing PD-L1 and Gal-9, which could restrict islet autoreactive T lymphocytes and protect β-cells from destruction. Intriguingly, overexpression of Gal-9 stimulated macrophage polarization to the M2 phenotype with immunosuppressive attributes. Alternatively, both PD-L1– and Gal-9–presenting aEVs (PD-L1–Gal-9 aEVs) favorably adhered to T cells via the interaction of programmed cell death protein 1/PD-L1 or T-cell immunoglobulin mucin 3/Gal-9. Moreover, PD-L1–Gal-9 aEVs prominently promoted effector T-cell apoptosis and splenic regulatory T (Treg) cell formation in vitro. Notably, PD-L1–Gal-9 aEVs efficaciously reversed new-onset hyperglycemia in NOD mice, prevented T1D progression, and decreased the proportion and activation of CD4⁺ and CD8⁺ T cells infiltrating the pancreas, which together contributed to the preservation of residual β-cell survival and mitigation of hyperglycemia. Article Highlights: Destruction of pancreatic β-cells by autoreactive CD4⁺ and CD8⁺ T cells is the main cause of type 1 diabetes (T1D); therefore, stunting autoreactive T cells is an effective strategy to alleviate T1D. Modulating the infiltration of T lymphocytes in the pancreas with exogenous programmed cell death ligand 1 (PD-L1) or galectin-9 (Gal-9) is an optimal treatment strategy for newly diagnosed T1D. PD-L1– and Gal-9–presenting (PD-L1–Gal-9) artificial extracellular vesicles (aEVs) exhibit characteristics of M2-type macrophages and efficaciously declined the proportion and activation of CD4⁺ and CD8⁺ T cells infiltrating the pancreas. PD-L1–Gal-9 aEVs demonstrated immunosuppressive therapeutic effects and effectively alleviated hyperglycemia in NOD mice with new-onset T1D. [ABSTRACT FROM AUTHOR]

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