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

Area of Science:

• Immunology
• Endocrinology
• Biotechnology

Background:

• Type 1 diabetes (T1D) development involves reduced immune checkpoint ligands, programmed cell death ligand 1 (PD-L1) and galectin-9 (Gal-9), in beta cells.
• Modulating pancreas-infiltrating T lymphocytes with PD-L1 or Gal-9 offers a therapeutic strategy for new-onset T1D.

Purpose of the Study:

• To engineer artificial extracellular vesicles (aEVs) overexpressing PD-L1 and Gal-9 to treat new-onset T1D.
• To investigate the immunomodulatory effects of PD-L1-Gal-9 aEVs on T cells and their therapeutic potential in a mouse model.

Main Methods:

• Genetically engineered macrophage cells to produce aEVs overexpressing PD-L1 and Gal-9.
• Assessed aEVs' interaction with T cells via PD-1/PD-L1 and TIM-3/Gal-9 pathways.
• Evaluated in vitro effects on effector T-cell apoptosis and regulatory T (Treg) cell induction.
• Administered aEVs to non-obese diabetic (NOD) mice with new-onset T1D.

Main Results:

• Overexpression of Gal-9 induced M2 macrophage polarization with immunosuppressive properties.
• PD-L1-Gal-9 aEVs demonstrated favorable adhesion to T cells and promoted effector T-cell apoptosis and Treg formation in vitro.
• PD-L1-Gal-9 aEVs effectively reversed hyperglycemia in NOD mice, prevented T1D progression, and preserved residual beta cells.
• Reduced infiltration and activation of pancreatic CD4+ and CD8+ T cells were observed in treated mice.

Conclusions:

• Engineered PD-L1-Gal-9 aEVs represent a promising therapeutic approach for new-onset T1D.
• These aEVs modulate T-cell responses and protect beta cells by restoring immune homeostasis.
• The study highlights the potential of cell-derived aEVs as targeted delivery vehicles for autoimmune disease treatment.