Purpose: Psoriasis is an inflammatory skin disease, where keratinocytes play pivotal roles in its pathogenesis. We prepared Celastrol Noisome hydrogel (Cel Nio gel) for the treatment of psoriasis and aimed to study its target site as well as the mechanism. Methods: Cel Nio was fabricated with thin-film hydration and sonication, then topically admi-nistered to imiquimod (IMQ)-induced psoriasis mice. The concentrations of Cel in the skin, blood and lymphatic system were determined using LC-MS. The anti-psoriasis effect of Cel Nio gel was studied, and the levels of inflammatory cytokines in blood were evaluated by flow cytometry. For the in vitro study, the uptake of Nio by HaCaT cells was quantified with flow cytometry, and the anti-inflammatory effect of Cel on HaCaT cells was detected with qPCR. The expressions of inflammatory factors and Ki-67 in skin were observed by immunofluorescence. Results: Cel Nio possessed a particle size of 133 nm with encapsulation efficacy (EE%) of 83.2%. After topical administration of Cel Nio gel to mice, Cel was mainly accumulated in the skin instead of exposure in blood or lymphatic system, while the levels of inflammatory factors in blood had a significant decline. In addition, the preparation of Nio enhanced the uptake by HaCaT cells, and Cel obviously reduced the mRNA levels of inflammatory cytokines in HaCaT cells. Moreover, Cel Nio gel significantly decreased the expression of inflammatory cytokines and Ki-67 in the skin. Conclusion: Cel Nio gel achieved the anti-psoriatic effect by inhibiting the inflammation and hyperproliferation of keratinocytes in the skin and further suppressing the systemic inflammation, thus could be a novel topical drug delivery system to treat psoriasis with topical and systemic effects.