The poor permeability of topically applied macromolecules such as small interfering RNA (siRNA) has inhibited the translation to clinical application. In this study, the fractional CO2 laser-assisted approach was developed to describe siRNA permeation enhancement mediated by the created microchannels for silencing the gene to treat psoriasiform lesions. In vitro permeation using Franz cell and in vivo interleukin (IL)-6 silencing using psoriasis-like plaque in mice were evaluated to verify the impact of the laser irradiation. Low-fluence laser exposure enabled a significant increase in skin transport of siRNA, peptide, and 5-fluorouracil (5-FU). The laser treatment resulted in the enhancement of siRNA flux by 33- and 14-fold as compared to the control in nude mouse and pig skin, respectively. The laser exposure also promoted siRNA penetration across psoriatic and photoaging skins with the deficient barrier, although the enhancement level was minor compared to that of intact skin. The 3D images of confocal microscopy revealed a diffusion of macromolecules into the laser-created microchannels; the radial and vertical distribution to the surrounding and deep tissues followed this. A single laser treatment and the following topical siRNA administration were able to reduce IL-6 expression by 64% in the psoriatic skin model. Laser assistance led to the marked improvement in the plaque and the reduction of specific cytokine expression, keratinocyte proliferation, and neutrophil infiltration. Our data support the use of the fractional laser for delivery of functional nucleic acid into the skin and the target cells.
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