Gold nanoparticles functionalized with 3-mercapto-1 -propansulfonate (AuNPs-3MPS) have been prepared and loaded with Methotrexate (MTX), an immunosuppressive agent used in the systemic treatment of moderate-severe inflammatory diseases. The effects of the AuNPs-3MPS@MTX topically administered in vitro on skin model and in vivo on imiquimod-induced psoriasis-like mice model, have been studied. Clinical response, epidermal thickness, cell proliferation rate and inflammation were tested. AuNPs-3MPS@MTX treated mice showed a decreasing of scaling and erythema score, reduction of epidermal thickness, parakeratosis and hyperkeratosis, compared to AuNPs3MPS treated mice. Immunnhistocheinistry analysis staining displayed that Ki67, K6 CD3 and CD8 stainings were reduced in AuNPs3MPS@MTX treated mice. Blood evaluation showed no differences in blood count and in ALT and AST levels before and after AuNPs3MPS or AuNPs-3MPS@MTX treatment. Topical AuNPs-3MPS@MTX treatment is able to induce a reduction of keratinocytes hyperproliferation, epidermal thickness and also inflammatory infiltrate in vivo on imiquimod-induced psoriasis like mice model. Published by Elsevier Inc.