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Synthetic fluorescein\u2010labeled amphiphilic peptides composed of the hydrophobic cell surface (cs) GRP78\u2010targeting and hydrophilic, polycationic arginine\u2010rich cell penetrating peptides demonstrated GRP78\u2010dependent cell uptake in the DU145 prostate cancer cells, and to a lesser extent in the non\u2010cancerous human lung fibroblast WI\u201038 cell line. Mechanistic studies revealed energy\u2010dependent GRP78 receptor\u2010mediated endocytosis of the GRP78\u2010targeting peptide with polyarginine (W1\u2010R9). The cytosolic accumulation of this peptide underscored its potential utility in siRNA delivery. Peptide:siRNA complexes formed stably condensed nanoparticles, with calcium functioning as an ionic stabilizer and additive promoting endosomal siRNA escape for RNA interference (RNAi) activity. Preliminary peptide\u2010based siRNA transfections in the DU145 cells demonstrated that GRP78 knockdown led to an interplay in between pro\u2010survival and cell death outcomes under ER stress induction. Thus, the GRP78\u2010targeting polyarginine peptides enables efficient cell uptake for specific siRNA delivery in the DU145 cells. This class of bio\u2010active synthetic peptides is important for the investigation of cancer biology, leading to the innovation of cancer\u2010targeted gene delivery and therapy approaches.<\/jats:p>","DOI":"10.1002\/psc.70007","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T07:05:51Z","timestamp":1739948751000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cancer\u2010Targeting Peptides Functionalized With Polyarginine Enables GRP78\u2010Dependent Cell Uptake and siRNA Delivery Within the DU145 Prostate Cancer Cells"],"prefix":"10.1002","volume":"31","author":[{"given":"George","family":"Hilan","sequence":"first","affiliation":[{"name":"Department of Biology Carleton University  Ottawa ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Daniel","sequence":"additional","affiliation":[{"name":"Department of Chemistry Carleton 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