BACKGROUND: Psoriasis is a chronic inflammatory skin disorder characterized by elevated levels of proinflammatory cytokines. Mesenchymal stem cells (MSCs) have demonstrated therapeutic potential, yet the specific mechanisms involved are not fully understood. OBJECTIVE: To investigated the effectiveness of extracellular vesicles (EVs) derived from MSCs that were genetically modified to overexpress miR-146a, in a mouse model of psoriasis. METHODS: To enhance miR-146a expression, MSCs were transfected, and their EVs were subsequently purified. Thirty mice were randomly assigned to three groups and induced with imiquimod cream to develop psoriasis-like skin lesions. The treatment groups included: (1) a control group administered PBS, (2) a group treated with EVs containing a control miRNA (miR-control EVs), and (3) a group receiving EVs enriched with miR-146a (miR-146a-EVs). EVs were administered intravenously and lesions were evaluated. Following intravenous administration of EVs, the severity of skin lesions was assessed. Concentrations of key cytokines, including IFN-γ, IL-17, TNF-α, IL-23, IL-6, IL-1β, TGF-β, IL-10, and IL-4, were quantified in both spleen and skin tissue lysates using ELISA and qRT-PCR techniques. RESULTS: The experimental findings demonstrated that the administration of miR-146a-enriched EVs led to a significant improvement in clinical symptoms. There were substantial reductions observed in combined erythema, scaling, and skin thickness measurements compared to untreated controls. Additionally, levels of proinflammatory cytokines IFN-γ, IL-17, TNF-α, IL-23, IL-6, and IL-1β were significantly downregulated in the miR-146a-EV group, while anti-inflammatory TGF-β, IL-10 and IL-4 were upregulated. The same results were obtained in the spleens of mice. CONCLUSION: EVs derived from miR-146a-modified MSCs effectively reduced psoriasis-like inflammation by modulating cytokine expression. This novel cell-free therapy holds promise for the treatment of psoriasis.