We developed elastic cationic liposomal vectors for transdermal siRNA delivery. These liposomes were prepared with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) as a cationic lipid and sodium cholate (NaChol) or Tween 80 as an edge activator. When NaChol or Tween 80 was included at 5, 10, and 15% (w/w) into DOTAP liposomal formulations (C5-, C10-, and C15-liposomes and T5-, T10-, and T15-liposomes), C15- and T10-liposomes showed 2.4- and 2.7-fold-higher elasticities than DOTAP liposome, respectively. Although the sizes of all elastic liposomes prepared in this study were about 80–90？nm, the sizes of C5-, C10- and C15-liposome/siRNA complexes (lipoplexes) were about 1,700–1,800？nm, and those of T5-, T10-, and T15-lipoplexes were about 550–780？nm. Their elastic lipoplexes showed strong gene suppression by siRNA without cytotoxicity when transfected into human cervical carcinoma SiHa cells. Following skin application of the fluorescence-labeled lipoplexes in mice, among the elastic lipoplexes, C15- and T5-lipoplexes showed effective penetration of siRNA into skin, compared with DOTAP lipoplex and free siRNA solution. These data suggest that elastic cationic liposomes containing an appropriate amount of NaChol or Tween 80 as an edge activator could deliver siRNA transdermally. 1. Introduction RNA interference (RNAi) offers potential for treating a wide variety of disorders through selective silencing of disease-relevant RNAs [1, 2]. Topical use of small interfering RNA (siRNA) has been increasingly studied for its applicability in treating skin disease [3]. However, transdermal naked siRNA delivery is limited due to its low permeability of skin barriers such as the stratum corneum and the epidermal layer. Liposomes have been widely investigated in dermatology as transdermal carrier systems [4]. Of particular interest are cationic liposomes for passive transdermal delivery of siRNA, since their opposite charges spontaneously result in complexation due to electrostatic interactions. Cationic liposomes protect siRNA from degradation and allow the introduction of siRNA into cells. It has been reported that elastic cationic liposomes (ultradeformable cationic liposomes) can penetrate intact skin while carrying plasmid DNA (pDNA) [5] and antisense oligonucleotides [6] when applied under nonoccluded conditions. Elastic cationic liposomes consist of a cationic lipid and an edge activator that is responsible for the elasticity of the membrane. An edge activator is usually a single-chain surfactant that destabilizes the lipid bilayers of the liposomes and
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