Artificial Tolerogenic Dendritic Cell-Derived Vesicles Prepared by High-Pressure Homogenization for Potent Immunotherapy of Type 1 Diabetes.

Abstract

Tolerogenic dendritic cells (tolDCs) have emerged as a promising immunotherapeutic approach for type 1 diabetes (T1D) by promoting immune tolerance and modulating autoimmune responses against pancreatic β cells. However, their clinical applications are challenged by various limitations including cell viability, scalability, and manufacturing complexities. As an alternative, tolDC-derived extracellular vesicles could address some limitations of cell-based therapies, though their application in T1D treatment remains unexplored. Here, we developed the artificial tolDC-derived vesicles (ACDV_tolDC) by a high-pressure homogenization approach, which retained immunosuppressive properties with high yield production and stability that improved the scalability for potential clinical use. In both chemically induced (STZ) and spontaneous (NOD) T1D mouse models, ACDV_tolDC exhibited abilities to reduce T cell infiltration by approximately 4-fold in the pancreas and re-establish the balance between regulatory and cytotoxic T cells to a healthy baseline, thereby preserving β cells and ameliorating T1D onset. Additionally, the therapeutic effect of ACDV_tolDC was superior to that of the tolDC treatment. These findings highlighted ACDV_tolDC as a potent vesicle-based immunotherapy for T1D, offering practical advantages over traditional tolDC therapies.