Editors' ChoiceDrug Delivery

Nanotransfection brings progress that’s more than skin-deep

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Science Translational Medicine  30 Aug 2017:
Vol. 9, Issue 405, eaao4216
DOI: 10.1126/scitranslmed.aao4216

Abstract

Arrayed nanochannels efficiently transfect skin for local in vivo genetic reprogramming.

The challenge of therapeutically delivering genetic material into tissues has slowed progress in the clinical adoption of RNA interference (RNAi), genomic editing, and cellular reprogramming technologies. Although viral transduction and nanoparticle-based methods have continued to improve, their ability to efficiently and reliably deliver large amounts of genetic material to specific solid tissue sites in vivo remains limited. For instance, many nucleic acid-based therapies require either ex vivo cell manipulation or are often confined to limited applications, such as hepatic delivery. Electroporation is the process of applying an electric field that transiently permeabilizes cell membranes and facilitates nucleic acid delivery, and it is one of the most widely used nonviral transfection technologies. Conventional bulk electroporation has long been demonstrated to transfect tissue; nonetheless, applicability in vivo has been narrow, in part due to poor efficiency. Recent efforts to miniaturize electroporation to the micro- and nanoscale have enhanced both efficacy and safety. Such miniaturization allows for the use of high intensity electric fields that locally yet non-toxically nanoporate cell membranes and electrophorese nucleic acids into the cell cytoplasm.

In a recent report, Gallego-Perez and colleagues expand on nanoscale transfection technologies to apply them to in situ transfection of skin tissue in mice. The authors designed a topically applied silicon wafer patterned with an array of 10 μm deep, ~500 nm wide nanochannels within larger microreservoirs. The wafer was combined with an intradermally injected electrode and then pulsed with 250 V at 10 ms intervals to drive DNA plasmids into epidermal cells. The approach elicited 50- to 250-fold greater gene expression in vivo compared with standard bulk electroporation methods. Interestingly, the device also caused transfected cells to produce extracellular vesicles containing complementary DNA and messenger RNA of the target genes, and these vesicles propagated transgene expression to neighboring cells.

In a series of demonstrations, the device was used to deliver 3-gene cocktails that transformed skin fibroblasts into either induced neurons (iN) or endothelial cells (iEC). Treatment with a newly developed cocktail for iEC rescued mouse hindlimbs from surgically induced necrotizing ischemia by promoting angiogenesis and limb perfusion. In both iN and iEC applications, the authors thoroughly validated cellular reprogramming biology through multiple molecular and imaging analyses. More work remains to analyze long-term safety and to compare the arrayed nanochannels with other advanced gene delivery technologies and gold standard therapies for treating ischemia. Gallego-Perez et al. demonstrate the potential of arrayed nanochannels to efficiently deliver plasmid cocktails to skin. This efficiency, coupled with the device simplicity, suggest broad applicability, including to surgically-accessed tissue sites, and compatibility with other genetic technologies.

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