Qbd-Engineered Brain-Targeted Mucoadhesive Lipid Nanocarriers of Rutin: In Vitro and In Vivo Evaluation

(1) Introduction: Rutin, a glycoside flavonoid that has high neuroprotective efficacy in neurodegenerative diseases, is hindered by low aqueous solubility and poor oral bioavailability. The major challenge in routine delivery is crossing the blood–brain barrier (BBB). So, to resolve these problems, in the present study, we formulate mucoadhesive nanolipid carriers (MNLCs) for intranasal administration for the purpose of enhancing residence time in the nasal cavity and targeting the brain by utilizing trigeminal and olfactory neuronal routes, thus avoiding the BBB. (2) Methodology: MNLCs were prepared using the melt emulsification and probe sonication technique, and various formulation parameters such as lipid content, surfactant concentration and sonication time were optimized using quality by design (QbD). A Box–Behnken design based on particle size, entrapment efficiency and drug release was utilized. Optimized nanocarriers were coated with β-cyclodextrin to impart mucoadhesive properties. Molecular docking was performed to evaluate the interaction of rutin with seven protein targets associated with Parkinson’s disease, while in vitro cytotoxicity was evaluated in HEK293 cells. In vivo pharmacodynamic evaluation was performed in rotenone-induced Wistar rats using locomotor activity, rotarod performance, brain TBARS, GSH, dopamine estimation, and histopathology. (3) Results: The characteristics of nanocarriers showed that the optimized MNLCs have a particle size of 150.8 42.5 nm, a polydispersity index of 0.592, a zeta potential of −18.2 mV and an entrapment efficiency of 92.4 ± 1.42%. The in vitro release profile demonstrated sustained release, with 80% drug release over 48 h, enhanced ex vivo permeation and acceptable cell viability at lower tested concentrations. SEM demonstrated the presence of cyclodextrin coating on the surface of the nanocarrier. The in vivo studies revealed increased brain delivery and therapeutic effect through nasal administration due to improvement in locomotor activity and motor coordination, reduced TBARS, and increased GSH and dopamine levels. Docking analysis identified interactions of rutin with the selected Parkinson’s disease-related protein targets, with the strongest reported score among the tested targets observed for IRAK4. (4) Conclusions: All results indicated that the cyclodextrin-coated MNLCs were successful in delivering rutin to the brain via intranasal administration and showed a sustained release profile with improved bioavailability and neuroprotection.