Topical delivery of siRNA into skin using SPACE-peptide carriers

J Control Release. 2014 Apr 10;179:33-41. doi: 10.1016/j.jconrel.2014.01.006. Epub 2014 Jan 13.


Short-interfering RNAs (siRNAs) offer a potential tool for the treatment of skin disorders. However, applications of siRNA for dermatological conditions are limited by their poor permeation across the stratum corneum of the skin and low penetration into the skin's viable cells. In this study, we report the use of SPACE-peptide in combination with a DOTAP-based ethosomal carrier system to enhance skin delivery of siRNA. A DOTAP-based SPACE Ethosomal System significantly enhanced siRNA penetration into porcine skin in vitro by 6.3±1.7-fold (p<0.01) with an approximately 10-fold (p<0.01) increase in epidermis accumulation of siRNA compared to that from an aqueous solution. Penetration of siRNA was also enhanced at the cellular level. Internalization of SPACE-peptide occurred in a concentration dependent manner marked by a shift in intracellular distribution from punctate spots to diffused cytoplasmic staining at a peptide concentration of 10mg/mL. In vitro delivery of GAPDH siRNA by SPACE peptide led to 83.3±3.0% knockdown relative to the control. In vivo experiments performed using female BALB/C mice also confirmed the efficacy of DOTAP-SES in delivering GAPDH-siRNA into skin. Topical application of DOTAP-SES on mice skin resulted in 63.2%±7.7% of GAPDH knockdown, which was significantly higher than that from GAPDH-siRNA PBS (p<0.05). DOTAP-SES formulation reported here may open new opportunities for cutaneous siRNA delivery.

Keywords: Cationic lipids; Cell penetrating peptide; Gene delivery; Silencing; Topical.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Cutaneous
  • Animals
  • Cells, Cultured
  • Epidermis / metabolism*
  • Fatty Acids, Monounsaturated / metabolism
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Transfer Techniques*
  • Glyceraldehyde-3-Phosphate Dehydrogenases / genetics
  • Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism
  • Humans
  • Keratinocytes / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Peptides / metabolism*
  • Permeability
  • Quaternary Ammonium Compounds / metabolism
  • RNA Interference*
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / metabolism*
  • Skin Absorption*
  • Swine


  • Fatty Acids, Monounsaturated
  • Peptides
  • Quaternary Ammonium Compounds
  • RNA, Small Interfering
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • 1,2-dioleoyloxy-3-(trimethylammonium)propane