PolySia Nanoparticle Modulates Macrophage Inflammation in Pathogenesis of Age-Related Macular Degeneration (AMD)

Document Type

Conference Proceeding

Publication Date

6-2025

Publication Title

Investigative Ophthalmology and Visual Science

Abstract

Purpose : The role of both cellular and non-cellular components of the innate immune system in the pathophysiology of AMD has been extensively studied. We are employing a novel therapeutic strategy to address chronic inflammation through the body's self-recognition system on immune cells. Our therapeutic molecule is a glycan-engineered nanoparticle with dual functions as previously shown to modulate complement and directly self-pattern recognition receptors on immune cells, known as Siglecs (sialic-acid binding immunoglobulin-like lectins). This dual action dampens the activity of inflammatory cells.

Methods : We analyzed the repolarization response of Polysialic acid (PolySia)-nanoparticles (NPs) using cell-based assays with PBMC-derived macrophages. Cells were stained with CD86 and CD163/CD206, an M1 and M2 macrophage marker, respectively, to assess macrophage polarization and phagocytosis using lysobrite. In addition to repolarization, the functional protection offered by PolySia-NP was evaluated in vivo using a laser-CNV model. Eight days post-laser CNV, mice were euthanized, and their eyes were enucleated and fixed. Choroidal flat-mounts were labeled with Isolectin-B4 and CD68 to assess the extent of neovascularization and the microglial inflammatory response, which were then examined via microscopy. Cytokine response was measured using IL-1β ELISA in RPE/choroid/sclera homogenates.

Results : Flow cytometry analysis revealed a dose dependent reduction in the M1/M2 ratio and an increase in CD163, indicating a shift towards an M2 phenotype with PolySia-NP treatment compared to controls. PolySia-NPs significantly decreased macrophage phagocytosis in-vitro and suppress IL-1β levels. CNV lesions immunolabeled with CD68, a lysosomal marker associated with phagocytosis, suggest that PolySia-NP may decrease microglial phagocytosis in this model.

Conclusions : PolySia-NPs significantly suppress IL-1β levels in the RPE/choroid/sclera homogenate from a laser-CNV model. Our in vitro data strongly support PolySia-NP's ability to repolarize activated macrophages from an M1 phenotype to a more resolving M2 phenotype. Additionally, PolySia-NPs appear to suppress phagocytosis in vitro and in vivo. Our data strongly support the potential of PolySia-NPs as a therapeutic approach for Age-related macular degeneration.

Volume

66

Issue

8

First Page

4330

Comments

Association for Research in Vision and Ophthalmology ARVO Annual Meeting, May 4-8, 2025, Salt Lake City, UT

Last Page

4330

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