A major challenge in treating neurological diseases is the blood-brain barrier (BBB), which prevents therapeutic molecules from entering the brain. This study demonstrates that a short peptide derived from rabies virus glycoprotein (RVG) enables transvascular delivery of small interfering RNA (siRNA) to the brain. The 29-amino-acid RVG peptide specifically binds to the acetylcholine receptor on neuronal cells. A modified RVG peptide (RVG-9R) with added arginine residues was synthesized to facilitate siRNA binding and transduction, resulting in efficient gene silencing in neuronal cells. After intravenous injection into mice, RVG-9R delivered siRNA to the brain, leading to specific gene silencing. Intravenous treatment with RVG-9R-bound antiviral siRNA provided robust protection against fatal viral encephalitis. Repeated administration of RVG-9R-bound siRNA did not induce inflammatory cytokines or anti-peptide antibodies, indicating a safe and noninvasive approach for delivering siRNA across the BBB. The BBB consists of tightly packed endothelial cells that prevent most molecules from entering the brain. Traditional gene therapy methods involve direct injection into the brain, which is invasive and limited in effectiveness. This study explored whether viral entry strategies could be used to deliver siRNA to the brain. RVG, which is known to interact with the acetylcholine receptor on neuronal cells, was tested for its ability to enable siRNA delivery. RVG-9R, a modified RVG peptide, was found to bind and deliver siRNA to neuronal cells in vitro and in vivo. RVG-9R enabled transvascular delivery of siRNA to the central nervous system, resulting in gene silencing in the brain. RVG-9R-bound siRNA was effective in silencing genes in the brain and protecting mice from viral encephalitis. The study also showed that RVG-9R could deliver siRNA to the brain without inducing inflammation or immune responses. These findings suggest that RVG-9R could be used for the delivery of siRNA and other therapeutic molecules across the BBB. The study highlights the potential of RVG-9R for targeted delivery of gene therapy vectors and small-molecule drugs to the brain.A major challenge in treating neurological diseases is the blood-brain barrier (BBB), which prevents therapeutic molecules from entering the brain. This study demonstrates that a short peptide derived from rabies virus glycoprotein (RVG) enables transvascular delivery of small interfering RNA (siRNA) to the brain. The 29-amino-acid RVG peptide specifically binds to the acetylcholine receptor on neuronal cells. A modified RVG peptide (RVG-9R) with added arginine residues was synthesized to facilitate siRNA binding and transduction, resulting in efficient gene silencing in neuronal cells. After intravenous injection into mice, RVG-9R delivered siRNA to the brain, leading to specific gene silencing. Intravenous treatment with RVG-9R-bound antiviral siRNA provided robust protection against fatal viral encephalitis. Repeated administration of RVG-9R-bound siRNA did not induce inflammatory cytokines or anti-peptide antibodies, indicating a safe and noninvasive approach for delivering siRNA across the BBB. The BBB consists of tightly packed endothelial cells that prevent most molecules from entering the brain. Traditional gene therapy methods involve direct injection into the brain, which is invasive and limited in effectiveness. This study explored whether viral entry strategies could be used to deliver siRNA to the brain. RVG, which is known to interact with the acetylcholine receptor on neuronal cells, was tested for its ability to enable siRNA delivery. RVG-9R, a modified RVG peptide, was found to bind and deliver siRNA to neuronal cells in vitro and in vivo. RVG-9R enabled transvascular delivery of siRNA to the central nervous system, resulting in gene silencing in the brain. RVG-9R-bound siRNA was effective in silencing genes in the brain and protecting mice from viral encephalitis. The study also showed that RVG-9R could deliver siRNA to the brain without inducing inflammation or immune responses. These findings suggest that RVG-9R could be used for the delivery of siRNA and other therapeutic molecules across the BBB. The study highlights the potential of RVG-9R for targeted delivery of gene therapy vectors and small-molecule drugs to the brain.