Psoriasis is a chronic inflammatory skin disease that affects 3% of the population, yet it is still without a cure. Safe and effective topical therapy is still lacking for this disease. Lerman et al discovered specific micro-RNAs (miRNAs), which can be an attractive therapeutic molecule for psoriasis. Although miRNA have the potential for treating psoriasis, its topical delivery to the depth of the epidermis is challenging due to the barrier properties of the top layer of the skin and the cell membrane. To overcome these obstacles and allow topical delivery of miRNA to skin cells, we suggested the use of ultrasound (US) as a mean to enhance biological membrane’s permeability (skin and cell), and quaternized starch (Q-starch) as a miRNA delivery carrier. In vivo experiments on humanized psoriatic mouse model verified that pre-treatment of the skin with US, allow efficient transdermal delivery of Q-starch-miRNA complexes . Furthermore the miRNA was biochemical active as it decreased the expression of the miRNA targets proteins. Moreover, a significant decrease in the psoriatic inflammatory markers has been visualized. Our results suggest that pre-treatment of the skin with US fallowed by topical administration of Q-starch-miRNA complexes could pave the way for future miRNA-based topical therapy.