Since hyaluronic acid (HA) has good biocompatibility and nonimmunogenicity, self-assembled hyaluronic acid nanoparticles (HA-NPs) have been widely used for a drug carrier combined with active agents. Recently, it has been reported that empty HA-NPs not bearing any drugs have therapeutic effects on adipose tissue inflammation and insulin resistance. In this study, I investigated effects of HA-NPs itself on psoriasis; chronic and relapsing inflammatory skin disease. HA-NPs is an amphiphilic molecule that is composed with hydrophobic lithocholic acid (LCA) and hydrophilic HA, so it is self-assembled in particles which have hydrophilic surface and hydrophobic core in aqueous environment. In the imiquimod (IMQ)-induced mouse psoriasis model, topical treatment with HA-LCA nanoparticles (HA-LCA NPs) effectively reduced IMQ-induced epidermal proliferation, abnormal differentiation, and macrophage infiltration. Using monocyte cell line, I found that HA-LCA NPs inhibit monocyte differentiation into pro-inflammatory M1 macrophage and reduce expression levels of tumor necrosis factor-alpha (TNF-α), which is the central player of inflammation and psoriasis and induces inflammatory cascades and hyper-proliferation of keratinocyte. In addition, HA-LCA NPs also down-regulated TNF-α and interferon-gamma-induced expression of pro-inflammatory cytokine genes in keratinocyte cell line. Thus, the skin-permeating HA-LCA NPs may serve as a new therapeutic agent for psoriasis treatment.