Targeting Siglecs with a sialic acid-decorated nanoparticle abrogates inflammation

Area of Science:

• Immunology
• Nanotechnology
• Pharmacology

Background:

• Sepsis and ARDS are leading causes of mortality with limited effective treatments.
• Siglec receptors (Siglec-E, Siglec-7, Siglec-9) are key negative regulators of inflammation.
• Targeting Siglec receptors presents a potential therapeutic strategy.

Purpose of the Study:

• To develop and evaluate a Siglec-targeting nanoparticle platform for treating inflammatory conditions like sepsis and ARDS.
• To investigate the mechanism of action of the nanoparticle on Siglec receptors and cytokine production.
• To assess the therapeutic efficacy of the nanoparticle in preclinical models.

Main Methods:

• Development of poly(lactic-co-glycolic acid) nanoparticles decorated with a Siglec ligand (α2,8 NANA-NP).
• Assessment of nanoparticle-induced Siglec-E oligomerization and cytokine production in murine macrophages.
• In vivo evaluation in murine models of sepsis and ARDS.
• In vitro and ex vivo human cell and lung perfusion models to confirm anti-inflammatory effects.
• Investigation of the role of interleukin-10 (IL-10) in nanoparticle efficacy.

Main Results:

• α2,8 NANA-NP induced enhanced Siglec-E oligomerization on macrophages compared to the free ligand.
• Nanoparticle treatment blocked lipopolysaccharide-induced inflammatory cytokine production in a Siglec-E-dependent manner.
• Therapeutic benefits were observed in vivo in sepsis and ARDS murine models.
• Anti-inflammatory effects were confirmed in human monocytes, macrophages, and an ex vivo lung injury model.
• Nanoparticle efficacy was dependent on IL-10, with the nanoparticle further augmenting IL-10 expression.

Conclusions:

• The Siglec-targeting nanoparticle platform demonstrates significant therapeutic potential for sepsis and ARDS.
• The nanoparticle effectively modulates inflammatory responses via Siglec-E and IL-10 pathways.
• This approach offers a promising novel strategy for managing critical inflammatory diseases.