To develop a small interfering RNA (siRNA) delivery system with low cytotoxicity and high transfection efficiency, siRNA was conjugated to poly(ethylene glycol) via a disulfide linkage (siRNA-PEG) to prepare polyelectrolyte complex micelles (PECMs) by condensing with a cationic fusogenic peptide (KALA). The siRNA-PEG conjugate exhibited enhanced resistance to degradation from nucleases. Anionic siRNA-PEG conjugate and cationic KALA, when mixed in an aqueous phase, spontaneously formed nano-sized PECMs (< 200 nm) that have an inner core of charge neutralized siRNA/KALA complex surrounded by a PEG corona. Vascular endothelial growth factor (VEGF) siRNA was used to demonstrate VEGF sequence-specific gene inhibition in prostate carcinoma cells (PC-3 cells). The extent of gene silencing was gradually increased with increasing nitrogen to phosphate (N/P) ratio and the concentration of siRNA-PEG/KALA PECMs. These results suggest that the formulation of siRNA-PEG/KALA PECMs could be widely applied for intracellular delivery of various therapeutic siRNAs. (c) 2007 Elsevier Inc. All rights reserved.