Skin diseases such as lupus, cancer, psoriasis, hyperhidrosis can potentially be treated effectively by suppressing allele-specific genes using small interfering RNA (siRNA). Injections of siRNA into skin, though effective, are painful and cover small surface areas and thus are not suitable as a long-term treatment option. Topical delivery of siRNA is an attractive alternative option to mediate RNA interference (RNAi). However, the barrier function of the epidermis impedes effective permeation of siRNA into the skin. Herein, we describe topical delivery of siRNA using ionic liquids (ILs) capable of complexing with siRNA non-covalently and delivering siRNA effectively. Using complementary and synergistic strategies of ionic liquids, we report delivery of effective doses of siRNA into the skin. The first strategy involved the use of hydrophobic cations to robe the siRNA whereas the second strategy involved the use of choline-geranic acid ionic liquid (CAGE) to enhance its dermal penetration. In vitro studies in porcine skin confirmed the synergistic effect of these strategies in enhancing epidermal and dermal penetration. In vivo application of siRNA formulation to SKH-1E hairless mice significantly suppressed Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression with no clinical evidence of toxicity. This strategy suggests a simple, personalized, and scalable platform for effective topical delivery of RNAi for treating genetic skin diseases.Copyright © 2019. Published by Elsevier B.V.