Skin Penetration Ability of Framework Nucleic Acids

It is surprising to see the penetration of framework nucleic acids or DNA origami in skin. It is amazing to find out that we can even control their penetration simply by tuning their size.

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Nucleic acid (NA), an integral component controlling cellular behaviours, hold tremendous potential when modulated. Over the past decade or so, we have seen increasing usage of NA interferences (NAi) for restoring altered cell functions. Being relatively large and anionic, NAi are conventionally loaded within certain carrier (e.g. polymeric, liposomal) for efficient cellular internalization. More recently, DNA origami, programmed folding of DNA strands into a 3D conformation (framework nucleic acids, FNA), have been experimented to enable “carrier-less” NA delivery into cells.

            One significant advantage of FNA is its highly-precise shape and size, promising consistent delivery efficiency. However, its in vivo application through systemic application have thus far been limited with its short lifespan, resulting in poor availability at disease site. Being a lab which specializes in transdermal diagnosis and drug delivery, through collaboration with the FNA expert Prof. Chunhai Fan, we set to explore whether topical application is an amiable route for FNA application, especially for local treatment of skin diseases like melanoma tumor (Figure 1).1

Figure 1. Framework nucleic acid (FNAs) as nanocarrier for transdermal drug delivery (TDD). a) FNAs with distinct shape and size between 20 to 200 nm are fabricated through programmed folding of DNA strands. b) Size-dependent skin penetration is observed, with 20 nm tetrahedral (TH21) FNAs penetrating the deepest from skin periphery. c) To prove its efficacy as TDD carrier, TH21 is intercalated with doxorubicin (DOX) to treat melanoma tumor model. d) TH21 successfully delivers DOX to tumor site, significantly more than topically-applied free DOX (tDOX) and comparable to when DOX is injected intratumorally (iDOX).      

            Evaluating 8 FNAs with distinct shape and size (ranging between 20-200nm), we noted size-dependent skin penetration of FNA, with 20nm tetrahedral FNAs (TH21) reaching well into the dermis region. In order to ascertain structural integrity during its penetration, we incorporated Förster resonance energy transfer (FRET) tagging mechanism into TH21. Evaluating its fluorescence across skin depth, minimal FRET deactivation suggested retention of integrity. Finally, we demonstrated its efficacy as transdermal drug carrier for doxorubicin melanoma treatment. Compared to other topical nanocarrier platforms, TH21 showed 2-fold enhanced efficacy stemming from its penetration.    

            While FNA colocalization with hair follicles in skin histology suggests role of appendages in facilitating its penetration, the extent to which it is regulated by FNA properties (size, shape, etc.) remains unclear. Naturally, the next step for this study is to elaborate more on FNA penetration mechanism. Ideally, we want a tight correlation between FNA physical properties with its penetration ability, allowing the generation of FNA ‘tool set’ for any particular desired depth. Besides, it will be interesting to explore its adaptation to pathological skin conditions requiring gene expression modulation, like keloid or hypethropic scarring. 



1. Wiraja, C. et al. Framework nucleic acids as programmable carrier for transdermal drug delivery. Nature Communications 10, 1147, doi:10.1038/s41467-019-09029-9 (2019).

Chenjie Xu

Assistant Professor, Nanyang Technological University