Engineering release kinetics with polyelectrolyte multilayers to modulate TLR signaling and promote immune tolerance

Area of Science:

• Immunology
• Materials Science
• Nanotechnology

Background:

• Autoimmune disorders arise from immune cells mistakenly attacking self-molecules.
• Aberrant inflammatory signaling via pathogen sensing pathways, like toll-like receptors (TLRs), is implicated in autoimmune diseases.
• Therapeutic inhibition of TLRs, particularly TLR9, shows promise for autoimmune conditions like multiple sclerosis (MS).

Purpose of the Study:

• To develop a sustained delivery system for GpG, a TLR9 antagonist, using degradable polyelectrolyte multilayers (PEMs).
• To investigate if Poly1/GpG PEMs can modulate inflammatory immune cell functions and promote tolerogenic responses.

Main Methods:

• Layer-by-layer assembly of degradable Poly1/GpG PEMs.
• Characterization of PEM degradation and GpG release kinetics.
• Assessment of GpG's biological activity post-release on dendritic cell activation, cytokine secretion, TLR9 signaling, and T cell polarization.

Main Results:

• Successful assembly and degradation of Poly1/GpG PEMs with sustained GpG release.
• Released GpG retained its ability to inhibit dendritic cell activation and inflammatory cytokine production.
• GpG effectively restrained TLR9 signaling and promoted a regulatory phenotype in myelin-specific T cells.

Conclusions:

• Degradable Poly1/GpG PEMs provide a viable strategy for sustained delivery of TLR9 antagonists.
• This approach can modulate immune cell function towards tolerance, offering potential therapeutic benefits for autoimmunity.
• The developed PEM system holds promise for treating autoimmune diseases by promoting tolerogenic immune responses.