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Background  Recent advances toward an effective therapy for prion diseases employ RNA interference to suppress PrP C  expression and subsequent prion neuropathology, exploiting the phenomenon that disease severity and progression correlate with host PrP C  expression levels. However, delivery of lentivirus encoding PrP shRNA has demonstrated only modest efficacy in vivo.    Methodology/Principal Findings  Here we describe a new siRNA delivery system incorporating a small peptide that binds siRNA and acetylcholine receptors (AchRs), acting as a molecular messenger for delivery to neurons, and cationic liposomes that protect siRNA-peptide complexes from serum degradation.    Conclusions/Significance  Liposome-siRNA-peptide complexes (LSPCs) delivered PrP siRNA specifically to AchR-expressing cells, suppressed PrP C  expression and eliminated PrP RES  formation in vitro. LSPCs injected intravenously into mice resisted serum degradation and delivered PrP siRNA throughout the brain to AchR and PrP C -expressing neurons. These data promote LSPCs as effective vehicles for delivery of PrP and other siRNAs specifically to neurons to treat prion and other neuropathological diseases.

Liposome-siRNA-Peptide Complexes Cross the Blood-Brain Barrier and Significantly Decrease PrPC on Neuronal Cells and PrPRES in Infected Cell Cultures