In situ nasal gel loaded with Lactoferrin-Coated Brexpiprazole nanostructured lipid carriers for Schizophrenia: Cross-Species validation in Ketamine-Induced rat and zebrafish models

Brexpiprazole (BXP), a third-generation antipsychotic, exhibits limited brain delivery following oral administration due to first-pass metabolism and blood–brain barrier constraints. To overcome these limitations, a Lactoferrin (Lf)-functionalized BXP-loaded nanostructured lipid carrier (Lf-BXP-NLC) incorporated into a thermoresponsive in situ nasal gel was developed to enable sustained and receptor-mediated nose-to-brain transport. The optimized formulation demonstrated nanoscale particle size (<200 nm), narrow polydispersity, high entrapment efficiency (∼88%), and physiological gelation temperature (30–34 °C), with preserved physicochemical stability over 3 months. In vitro release and ex vivo permeation studies confirmed controlled drug release and enhanced mucosal transport. In vivo pharmacokinetic evaluation in rats revealed significantly improved brain exposure following intranasal administration, with approximately 1.9-fold higher AUC brain compared with drug suspension and 1.97-fold greater exposure relative to intravenous delivery. A rapid brain T max (0.41 h) and direct transport percentage of ∼ 62% indicated dominant neuronal pathway involvement and reduced reliance on systemic circulation. Enhanced pharmacokinetics translated into pronounced pharmacodynamic benefits in ketamine-induced schizophrenia models, including significant attenuation of stereotypic behaviors, restoration of motor coordination, and near-normalization of neuromuscular performance. Cross-species validation in zebrafish further demonstrated substantial correction of anxiety-like behavior and cognitive impairment, reinforcing translational robustness. Importantly, no nasal ciliotoxicity was observed. Collectively, this multifunctional intranasal nanocarrier platform achieves rapid, sustained, and targeted brain delivery of BXP and offers a promising non-invasive strategy for precision neuropsychiatric therapy.