Naked DNA and Hair Follicles
Surprisingly, topically applying naked DNA to skin or exposed mucus membranes actually has some precedent and some interesting successes.
In 2000, Alexeev et al. demonstrated that topical application of an RNA-DNA oligonucleotide could partially reverse a mouse's albinism! The albinism was due to a point mutation that the oligo reversed. In other words, by topically applying a substance to the mouse's skin they changed the genome of the mouse. I always thought that this would be a cool way to dye your hair.
There are limitations when applying drugs transdermally: "The approximately 20 drugs with approval from the Food and Drug Administration (FDA) as transdermal patches all have molecular weights below 400 Da, are relatively lipophilic and require low doses" (Kim et al.).
This 2011 paper by Yu et al. goes into more detail about plasmid uptake through hair follicles. As you may expect, damaging the skin (e.g., chemically or by hair plucking) improves plasmid uptake.
In this 2006 review, they describe a very nice experiment to find the peptide that best overcomes the skin barrier in mice. As shown in the diagram above, they simply apply a phage library to the mouse, harvest the phage most successful at crossing the skin barrier and entering the blood. The winning peptide is a simple 11mer: ACSSSPSKHCG!
It's intriguing to think about combining these methods to improve the efficiency of DNA vaccine uptake transdermally.