Metabolite releasing polymers control dendritic cell function by modulating their energy metabolism

Area of Science:

• Immunometabolism
• Immunotherapy
• Cellular Metabolism

Background:

• Metabolites are crucial regulators of immune cell functions.
• Sustained delivery of metabolites can modulate immune cell activity.
• Alpha-ketoglutarate (aKG) plays a role in cellular metabolic pathways.

Purpose of the Study:

• To synthesize polymeric-microparticles for sustained release of alpha-ketoglutarate (aKG).
• To investigate the effects of aKG-loaded microparticles (paKG MPs) on dendritic cell (DC) metabolism and immune phenotype.
• To explore the potential of this immunometabolism strategy for immunotherapy.

Main Methods:

• Synthesis of diol-based polymeric-microparticles loaded with alpha-ketoglutarate (aKG).
• In vitro incubation of dendritic cells (DCs) with paKG MPs.
• Analysis of intracellular metabolic profiles, including glycolysis and mitochondrial respiration.
• Flow cytometry assessment of DC surface markers (MHC-II, CD86) and T cell populations (Tregs, Th1/2/17).

Main Results:

• paKG MPs successfully delivered aKG and modulated intracellular metabolic pathways in DCs.
• aKG delivery led to decreased glycolysis and mitochondrial respiration in DCs.
• Metabolic changes in DCs resulted in altered expression of MHC-II and CD86.
• In vitro studies showed modulation of regulatory T cells (Tregs) and T-helper type-1/2/17 cell frequencies.

Conclusions:

• Sustained intracellular delivery of aKG using paKG MPs can suppress immune cell metabolism and function.
• This approach offers a novel strategy for immunometabolism-based immunotherapy.
• The findings suggest potential applications in treating diseases associated with immune dysregulation.