Topical administration is attractive and non-invasive gene delivery approach. It is simple and allows repeated administration.
In addition, the skin is active immune surveillance site. Topical gene therapy, although promising for treatment of cancer, dermatological
disorders, vaccination and autoimmune disease, has not progressed yet to clinical trials. The inability of nucleic acids to survive the extraand
intracellular environment and to permeate through the outermost layer of the skin, the stratum corneum, compromise the therapeutic
outcomes of nucleic acids-based therapies. Nanostructured vehicles (e.g. transfersomes, niosomes, nanoemulsions, gemini-lipid nanoparticles
and biphasic vesicles) have the ability to partially disrupt and perturb lipids that are found in the skin layers and deliver their nucleic
acid cargos to their targeted subcellular compartments. However, the efficiency of these carriers is still inferior to other invasive
methods (e.g. epidermal and intradermal injections). The goal of this review is to examine the critical parameters required to enhance the
efficiency of the currently available nanostructured vehicles, for example, by combining them with minimally invasive techniques, such
as, electroporation, iontophoresis, microneedles, ultrasound, gene gun and femtosecond laser. The recent advances in engineering these
nanovectors will be discussed with a focus on their future prospects.