Rotigotine is a non-ergoline, potent and selective dopaminergic (D2) receptor agonist which is highly effective for the treatment of early Parkinson's disease. Despite the therapeutic potential, its long-term clinical practice has been hindered because of poor oral bioavailability (1%), extensive first-pass metabolism and short plasma half-life (5 to 7 hours). The aim of this study was to develop and characterise rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery. The RNPs were prepared by ionic gelation technique. Optimised RNPs had small particle size (75.37±3.37 nm), low polydispersity index (PDI) (0.368±0.024), high zeta potential (+25.53±0.45 mV) and high entrapment efficiency (%EE) (96.08±0.01%). Solid-state characterisation studies include transmission electron microscopy (TEM), scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and Fourier-transform infrared (FT-IR) spectroscopy. In vitro release and ex vivo nasal permeation of rotigotine from RNPs was 49.45±2.09% and 92.15±4.74% respectively. Effect of RNPs on the integrity of mucosa was evaluated using nasal mucosal from goat. The histopathological changes in the treated and untreated nasal mucosa after 24 h of drug permeation was analysed using light microscopy. The histopathological study showed that there was no toxicity or structural damage to nasal mucosa due to exposure to the RNPs. Cytotoxicity of RNPs on cultured cells was evaluated by treating human neuroblastoma SH-SY5Y cells with this preparation for 24-hours using the MTT cell proliferation assay. Cell viability was more than 90% after 24- hours of exposure to the RNPs. Treatment of SH-SY5Y cells showed significant neuroprotective effect (P<0.01) against 6-hydrodopamine (6-OHDA)-induced neurotoxicity. Furthermore, RNPs were found to up-regulate the levels of dopamine, tyrosine hydroxylase (TH), superoxide dismutase (SOD) as well as down-regulate the levels of !-synuclein (SNCA) and reactive oxygen species (ROS) in the SH-SY5Y neuroblastoma cells. The results indicate that RNPs are a promising carrier for noseto- brain delivery. In vivo behaviour of these nanoparticulate carriers should be further evaluated in animal models of Parkinson's disease.