Neurodegeneration is characterized by progressive loss of structure and function of neurons. Several therapeutic methods and drugs are available to alleviate the symptoms of these diseases. The currently used delivery strategies such as implantation of catheters, intracarotid infusions, surgeries, and chemotherapies are invasive in nature and pose a greater risk of postsurgical complications, which can have fatal side effects. The current study utilizes a peptide (TAT and MGF) tagged PEGylated chitosan nanoparticle formulation for siRNA delivery, administered intranasally, which can bypass the blood brain barrier. The study investigates the optimal dose, duration, biodistribution, and toxicity, of the nanoparticle-siRNA formulation, in-vivo. The results indicate that 0.5？mg/kg of siRNA is delivered successfully to the hippocampus, thalamus, hypothalamus, and Purkinje cells in the cerebellum after 4？hrs of post intranasal delivery. The results indicate maximum delivery to the brain in comparison to other tissues with no cellular toxic effects. This study shows the potential of peptide-tagged PEGylated chitosan nanoparticles to be delivered intranasally and target brain tissue for the treatment of neurological disorders. 1. Introduction Blood brain barrier (BBB) is the major challenge that limits the application of neurotherapeutics for the treatment of neurological disorders [1]. The BBB is formed by a membranous network of brain capillary endothelial cells (BCEC), connected through tight junctions [2]. This physiological barrier imposes a selective permeability to various molecules and substances. This close-knit microenvironment is however essential to protect central nervous system (CNS) from the intrusion of harmful chemical/substances, but it poses a challenge for the delivery of neuroprotective drugs for the treatment of neurological disorders [3]. Systemic administration of various neuropeptides and hydrophilic therapeutic agents, such as antibiotics and anticancer agents, has failed to cross the BBB [4]. The CNS only allows small, lipophilic compounds (<400–500？Da) to permeate and cross the BBB [1]. The cerebrovasculature of CNS has a large surface area of approximately 20？m2, which allows successful drug administration via transendothelial route, provided that the physiological barrier could be overcome. Current clinical strategies include surgical interventions, which are invasive and can later pose postsurgical complications with fatal side effects [5]. Some of the currently employed invasive approaches (mechanically breaching the BBB) include
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