Non-Invasive Transdermal Delivery of Antisense Oligonucleotides with Biocompatible Ionic Liquids

Nucleic acid drugs, including antisenseoligonucleotides (ASOs),have received considerable attention as novel therapeutics for thetreatment of intractable diseases. Despite their potential benefits,ASOs are currently administered via injection, which can negativelyimpact patient quality of life because of the prevalence of severeinjection site reactions. Non-invasive transdermal administrationof ASOs is desirable but highly challenging owing to the strong barrierimposed by the stratum corneum, which only permits the penetrationof small molecules under 500 Da. For ASOs to exert their antisenseeffect, they must traverse the negatively charged cell membrane andreach the cytoplasm. In this study, we used the solid-in-oil (S/O)dispersion technology to facilitate the skin permeation of ASOs bycoating the drug with a hydrophobic surfactant molecule, specificallylipid-based ionic liquid (IL) surfactants with high biocompatibilityand transdermal penetration-enhancing properties. To induce the antisenseeffect, it was important to achieve simultaneous transdermal deliveryand intracellular entrapment of ASOs. In vitro investigations indicatedthat the newly prepared IL-S/O enhanced the transdermal penetrationand intracellular delivery of ASOs, thus inhibiting mRNA translationof the target TGF-& beta;. In addition, in vivo investigations oftumor-bearing mice suggested that the anti-tumor effect of the IL-S/Owas similar to that of injection. This study demonstrates the potentialof non-invasive transdermal delivery carriers based on biocompatibleILs, which can be applied to a variety of nucleic acid drugs.

Automated summary

Nucleic acid drugs, such as antisense oligonucleotides (ASOs), have shown great potential as therapeutics for intractable diseases. However, their current administration via injection can negatively impact patient quality of life. This study introduces a transdermal delivery method using lipid-based ionic liquid surfactants, which enhance the skin permeation and intracellular delivery of ASOs. In vitro and in vivo experiments demonstrate the effectiveness of this approach in inhibiting tumor growth.