Ren, YinHauert, SabineLo, Justin H.Bhatia, Sangeeta2013-04-082012Ren, Yin, Sabine Hauert, Justin H. Lo, and Sangeeta N. Bhatia. 2012. Identification and characterization of receptor-specific peptides for siRNA delivery. ACS Nano 6(10): 8620-8631.1936-0851http://nrs.harvard.edu/urn-3:HUL.InstRepos:10511099Tumor-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.en-USsiRNA deliverytumor-penetrating peptidescell-penetrating peptidesLyP-1cancer therapyJournal Article2013-04-0810.1021/nn301975s