Identification and characterization of receptor-specific peptides for siRNA delivery.
Tumor-targeted delivery of siRNA remains a major barrier in fully realizing the therapeutic potential of RNA interference. While cell-penetrating peptides (CPP) are promising siRNA carrier candidates, they are universal internalizers that lack cell-type specificity. Herein, we design and screen a library of tandem tumor-targeting and cell-penetrating peptides that condense siRNA into stable nanocomplexes for cell type-specific siRNA delivery. Through physiochemical and biological characterization, we identify a subset of the nanocomplex library of that are taken up by cells via endocytosis, trigger endosomal escape and unpacking of the carrier, and ultimately deliver siRNA to the cytosol in a receptor-specific fashion. To better understand the structure-activity relationships that govern receptor-specific siRNA delivery, we employ computational regression analysis and identify a set of key convergent structural properties, namely the valence of the targeting ligand and the charge of the peptide, that help transform ubiquitously internalizing cell-penetrating peptides into cell type-specific siRNA delivery systems.
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Yin
Y
Ren
Sabine
S
Hauert
Justin H
JH
Lo
Sangeeta N
SN
Bhatia
D006367:HeLa Cells; D006801:Humans; D053769:Nanocapsules / Q000737:chemistry / Q000627:therapeutic use*; D009374:Neoplasms, Experimental / Q000503:physiopathology* / Q000628:therapy; D019151:Peptide Library; D010455:Peptides / Q000493:pharmacokinetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014162:Transfection / Q000379:methods*
D053769:Nanocapsules; D019151:Peptide Library; D010455:Peptides; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface