siRNA Therapeutics for Protein Misfolding Diseases of the Central Nervous System.

Nanoparticles have been used to deliver siRNA to tissues and cells to silence specific genes in diverse organisms. Research and clinical application of nanoparticles like liposomes for drug delivery requires targeting them to specific anatomic regions or cell types, while avoiding off-target effects or clearance by the liver, kidney, or the immune system. Delivery to the central nervous system (CNS) presents additional challenges to cross the blood-brain barrier (BBB) to specific cell types like neurons, astrocytes, or glia. 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 or instilled intranasally, 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.