Self-assembled hyaluronic acid nanoparticles target TLR2 to regulate macrophage M1 polarization and alleviate psoriasis

Self-assembled hyaluronic acid nanoparticles (HANPs) possess unique biocompatibility and receptor-binding properties, making them widely studied as drug delivery systems. Notably, empty HANPs alone have demonstrated therapeutic and ameliorative effects in various inflammatory diseases. In this study, we conjugated hyaluronic acid and 5βcholanic acid to create self-assembled nanoparticles (HACNs). We then investigated the effects of HACNs on macrophage polarization towards the pro-inflammatory M1 phenotype using mouse primary bone marrow-derived macrophages and the human monocyte cell line THP-1 cells. Our findings reveal that HACNs directly interact with Toll-like receptor 2 (TLR2) and effectively suppress the expression of pro-inflammatory mediators by competitively inhibiting ligand-receptor interactions in macrophages. This inhibitory effect on TLR2 signaling is mainly due to the spherical structure of the selfassembled hydrophilic hyaluronic acid (HA) shell, rather than to free HA or the hydrophobic core component, 5β-cholanic acid. Furthermore, the protective effects of HACNs against IMQ-induced epidermal hyperplasia and elevated pro-inflammatory cytokine levels were significantly diminished in TLR2-defecient mice. These results highlight the potential of empty HACNs as effective therapeutic agents for TLR2- mediated inflammatory disorders.