The study demonstrates a novel method for delivering small interfering RNA (siRNA) to the central nervous system (CNS) by transvascular means, overcoming the blood-brain barrier (BBB). The researchers used a short peptide derived from the rabies virus glycoprotein (RVG) that specifically binds to the acetylcholine receptor on neuronal cells. By adding nonamer arginine residues at the carboxy terminus of RVG, they created a chimaeric peptide called RVG-9R, which effectively binds and delivers siRNA to neuronal cells in vitro and in vivo. Intravenous injection of RVG-9R-bound siRNA in mice resulted in specific gene silencing within the brain, protecting against fatal viral encephalitis. The approach was safe, noninvasive, and did not induce inflammatory responses or anti-peptide antibodies. This study highlights the potential of RVG-9R for delivering siRNA and other therapeutic molecules across the BBB to treat neurological diseases.The study demonstrates a novel method for delivering small interfering RNA (siRNA) to the central nervous system (CNS) by transvascular means, overcoming the blood-brain barrier (BBB). The researchers used a short peptide derived from the rabies virus glycoprotein (RVG) that specifically binds to the acetylcholine receptor on neuronal cells. By adding nonamer arginine residues at the carboxy terminus of RVG, they created a chimaeric peptide called RVG-9R, which effectively binds and delivers siRNA to neuronal cells in vitro and in vivo. Intravenous injection of RVG-9R-bound siRNA in mice resulted in specific gene silencing within the brain, protecting against fatal viral encephalitis. The approach was safe, noninvasive, and did not induce inflammatory responses or anti-peptide antibodies. This study highlights the potential of RVG-9R for delivering siRNA and other therapeutic molecules across the BBB to treat neurological diseases.