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 extra- and 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.