Delivery of small interfering RNA by peptide-targeted mesoporous silica nanoparticle-supported lipid bilayers

Carlee E. Ashley, Eric C. Carnes, Katharine E. Epler, David P. Padilla, Genevieve K. Phillips, Robert E. Castillo, Dan C. Wilkinson, Brian S. Wilkinson, Cameron A. Burgard, Robin M. Kalinich, Jason L. Townson, Bryce Chackerian, Cheryl L. Willman, David S. Peabody, Walker Wharton, C. Jeffrey Brinker

Research output: Contribution to journalArticlepeer-review

184 Scopus citations

Abstract

The therapeutic potential of small interfering RNAs (siRNAs) is severely limited by the availability of delivery platforms that protect siRNA from degradation, deliver it to the target cell with high specificity and efficiency, and promote its endosomal escape and cytosolic dispersion. Here we report that mesoporous silica nanoparticle-supported lipid bilayers (or " protocells") exhibit multiple properties that overcome many of the limitations of existing delivery platforms. Protocells have a 10- to 100-fold greater capacity for siRNA than corresponding lipid nanoparticles and are markedly more stable when incubated under physiological conditions. Protocells loaded with a cocktail of siRNAs bind to cells in a manner dependent on the presence of an appropriate targeting peptide and, through an endocytic pathway followed by endosomal disruption, promote delivery of the silencing nucleotides to the cytoplasm. The expression of each of the genes targeted by the siRNAs was shown to be repressed at the protein level, resulting in a potent induction of growth arrest and apoptosis. Incubation of control cells that lack expression of the antigen recognized by the targeting peptide with siRNA-loaded protocells induced neither repression of protein expression nor apoptosis, indicating the precise specificity of cytotoxic activity. In terms of loading capacity, targeting capabilities, and potency of action, protocells provide unique attributes as a delivery platform for therapeutic oligonucleotides.

Original languageEnglish (US)
Pages (from-to)2174-2188
Number of pages15
JournalACS Nano
Volume6
Issue number3
DOIs
StatePublished - Mar 27 2012
Externally publishedYes

Keywords

  • cancer
  • lipid nanoparticle
  • mesoporous silica nanoparticle
  • peptide ligand
  • small interfering RNA
  • supported lipid bilayer
  • targeted delivery

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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