Transferrin-Functionalized Chitosan Nanoparticles Enable Intranasal Brain Delivery of Cariprazine with Enhanced Neuropharmacological Efficacy

Transferrin-functionalized chitosan nanoparticles (TfCZNP) were developed for the intranasal delivery of Cariprazine to enhance brain targeting and minimize systemic exposure. The optimized nanoparticles exhibited favorable physicochemical properties (size, 207 nm; PDI, 0.403; zeta potential, +34.1 mV) with confirmed transferrin conjugation (gel electrophoresis, surface plasmon resonance, and FTIR spectroscopy) and uniform morphology (TEM). TfCZNP showed sustained in vitro release, improved ex vivo nasal permeation, and excellent biocompatibility. Gamma-scintigraphy revealed preferential brain accumulation (44 ± 4%) with a minimal systemic distribution. Pharmacokinetics demonstrated higher brain exposure (<i>C</i>_max 132.35 ± 7.79 ng/mL; AUC_0-24h 498.67 ng·h/mL) and favorable targeting indices (DTE 6.26, DTI 6.04, direct transport percentage 90.69%) versus controls. Behavioral studies in ketamine-induced schizophrenia models confirmed the normalization of locomotor activity, anxiolytic effects, and reduced catalepsy. These findings establish TfCZNP as a safe, effective nose-to-brain delivery platform that enhances Cariprazine's therapeutic potential in neuropsychiatric disorders.