Blockade of TLR2 activation in macrophages by self-assembled hyaluronic acid nanoparticles alleviates psoriasis-like skin dermatitis.

Self-assembled hyaluronic acid nanoparticles (HANPs) exhibit promising therapeutic effects against psoriasis, yet their precise targets and molecular mechanisms remain inadequately explored. Here, we demonstrate that HANPs target toll-like receptor 2 (TLR2) to alleviate psoriatic skin inflammation in preclinical settings. This action is mediated by the HA-derived hydrophilic shell surrounding the NPs, rather than free HA or the hydrophobic core. Mechanistically, HANPs inhibited TLR2-driven macrophage differentiation into the pro-inflammatory M1 phenotype, suppressing Il1b, Tnf, and Nlrp3 expression by 60-80 %. HANPs also blocked downstream NF-κB, MAP kinase, and NLRP3 inflammasome activation, leading to a ∼65 % reduction in mature IL-1β secretion. Importantly, TLR2 expression was markedly elevated in the psoriatic skin of both mouse models and human patients. Transcutaneous administration of HANPs significantly alleviated imiquimod-induced psoriasis-like dermatitis, reducing epidermal thickness by ∼35 %, improving skin barrier function, and exhibiting no observable toxicity. Notably, these therapeutic effects were not observed in Tlr2-deficient mice, confirming the specificity of TLR2 targeting by HANPs. Our findings uncover the anti-inflammatory mechanism of HANPs and position them as a promising strategy for psoriasis therapy.