Lipopeptide Delivery of siRNA to the Central Nervous System.

RNA interference is a relatively new tool used to silence specific genes in diverse biological systems. The development of this promising new technique for research and therapeutic use in studying and treating neurological diseases has been hampered by the lack of an efficient way to deliver siRNA transvascularly across the blood-brain barrier (BBB) to the central nervous system (CNS). Here we describe the generation of three different liposomal siRNA delivery vehicles to the CNS using the thin film hydration method. Utilizing cationic or anionic liposomes protects the siRNA from serum nucleases and proteases en route. To deliver the siRNA specifically to the CNS, the liposomes are complexed to a peptide that acts as a neuronal address by binding to nicotinic acetylcholine receptors (nAchRs). When injected intravenously, these liposome-siRNA-peptide complexes (LSPCs) or peptide addressed liposome encapsulated therapeutic siRNA (PALETS) resist serum degradation, effectively cross the BBB and deliver siRNA to AchR-expressing cells to suppress protein expression in the CNS.