Delivery of small interfering RNA by peptide-targeted mesoporous silica nanoparticle-supported lipid bilayers.
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.
Biotechnology and Bioengineering Department, Sandia National Laboratories, Livermore, California 94551-0969, USA. ceashle@sandia.gov or
Carlee E
CE
Ashley
Eric C
EC
Carnes
Katharine E
KE
Epler
David P
DP
Padilla
Genevieve K
GK
Phillips
Robert E
RE
Castillo
Dan C
DC
Wilkinson
Brian S
BS
Wilkinson
Cameron A
CA
Burgard
Robin M
RM
Kalinich
Jason L
JL
Townson
Bryce
B
Chackerian
Cheryl L
CL
Willman
David S
DS
Peabody
Walker
W
Wharton
C Jeffrey
CJ
Brinker
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D020868:Gene Silencing; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000378:metabolism*; D016062:Porosity; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012822:Silicon Dioxide / Q000737:chemistry*; D014162:Transfection / Q000379:methods*
D008051:Lipid Bilayers; D010455:Peptides; D034741:RNA, Small Interfering; D012822:Silicon Dioxide