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The skin is the largest organ in the body and an obvious route for both local and systemic drug delivery. Antisense oligomers have tremendous potential as therapeutic agents for numerous diseases. The objective of this study was to investigate the influence of vehicle on the transdermal delivery of several phosphorodiamidate Morpholino oligomers (PMOs) with different sizes, lengths, base compositions, sequences, and lipophilicities. Eleven different PMOs were synthesized complementary to biologically relevant gene targets and delivered across hairless mouse skin in vitro using vehicles composed of 95% propylene glycol, 5% linoleic acid (PG/LA), water, 50% water:50% PG/LA, and 75% water:25% PG/LA. The data suggest that size, sequence and guanine composition all influence transdermal penetration. There was an inverse linear relationship between size and penetration for a given sequence when the PG/LA formulation was used (r2 = 0.94), but this trend was not evident when the vehicle contained water. An oligomer targeted to the gene p53 had lower than expected transdermal penetration based on its size, but was shown to localize within the skin, demonstrating that sequence and thus target will impact transdermal delivery. The presence of G-quartets correlated with better PMO penetration from a water vehicle. Overall, the data suggest that some oligomers and vehicles would be better for transdermal delivery and others for topical applications.