Sialic acid-targeting strategies to understand its role in inflammation and arthritis

Doctoral thesis, 2026

Sialic acid (Sia) is a monosaccharide increasingly recognized for its pathological roles in diseases such as cancer, autoimmune disorders, and osteoarthritis (OA). Positioned at the terminal ends of glycans, Sia serves as a key interface for cellular interactions and immune regulation through engagement with Sia-binding immunoglobulin-like lectins (Siglecs). Although the role of Sia in OA remains poorly defined, altered Sia expression has been reported on chondrocytes, in synovial fluid, and on lubricin, supporting its involvement in inflammatory processes. Despite the complexity of OA, disease-modifying therapeutics remain limited. The disease is characterized by cartilage degeneration and chronic inflammation, with monocytes and macrophages playing key roles. This thesis aims to elucidate the immunoregulatory functions of Sia and evaluate its potential as a target for disease-modifying strategies using nanotechnology.

Given the emerging evidence for Sia involvement in OA, improved understanding of the spatiotemporal dynamics of Sia and associated pathways may enable targeted immunomodulation. We identified the presence of Siglec-5/14 in OA synovial fluid, suggesting a functional role in disease. First, focusing on monocytes, a previously uncharacterized immunoregulatory role of Siglec-5 in modulating pro-inflammatory toll-like receptor 4 (TLR4) signaling was identified. Second, we observed inflammation-induced alterations in Sia metabolism which did not correspond with increased cell-surface Sia. Lastly, using an enzyme-based cartilage degradation model, we showed that Sia removal led to cartilage breakdown, reinforcing its importance for cartilage integrity. Together, these findings provide mechanistic insight into the role of Sia in OA pathogenesis.

Building on these findings, Sia, pH changes, and cartilage degradation products were utilized for selective targeting and controlled drug release using polymeric nanoparticles (PNPs). Functionalization with phenylboronic acid (PBA) enabled multivalent and reversible binding to Sia, resulting in measurable immunomodulatory effects on monocyte migration in a transwell assay. Furthermore, pH-responsive drug release was demonstrated in a relevant biological model, underscoring its applicability in inflammation. Finally, glycosylation within the biomolecular corona influences nanoparticle-microenvironment interactions, with glycan structures emerging as key determinants of nanoparticle behavior and therapeutic performance.

Collectively, these findings highlight a mechanistic role for sialylation in inflammation and support glycan-targeting strategies as a foundation for Sia-directed immune modulation in OA.