Niosomal Bupropion: Exploring Therapeutic Frontiers through Behavioral Profiling Bupropion (Bup) is a norepinephrine–dopamine reuptake inhibitor (NDRI) and the only FDA-approved drug of its class for treating major depressive disorder (MDD), sold as Wellbutrin. While effective, regular use and overdose can lead to seizures and liver failure. To improve efficacy and reduce dosing, this study nanoformulated Bup into niosomal vesicles. The thin film hydration method was used to synthesize and optimize Bup-loaded niosomes with three surfactants (Span 20, 40, 60) and cholesterol. The optimal niosome formulation was found to have a cholesterol-to-surfactant ratio of 1:1.5, with Bup@N₂O (Span 20) showing minimal toxicity and sustained Bup release in artificial cerebrospinal fluid (ACSF). The Bup@N₂O formulation improved exploration activity and reduced irregular movements in reserpine-induced depression in adult zebrafish, indicating potential for mood improvement. It outperformed the positive control group and was comparable to the control group, suggesting niosomal Bup as a promising delivery system for brain delivery by bypassing the blood-brain barrier. The study focused on optimizing cholesterol and surfactant concentrations for niosome stability and drug encapsulation. The optimal cholesterol concentration was 1 μM, and the optimal surfactant concentration was 1.5 μM. FTIR analysis confirmed niosome formation and Bup encapsulation. Stability studies showed minimal changes in vesicle size and PDI over 28 days. Scanning electron microscopy revealed spherical morphology with a size of 62 nm for Bup@N₂₀C. Bup release in ACSF showed sustained release, indicating enhanced therapeutic index. Behavioral analysis of adult zebrafish showed improved activity in the study groups, with NF1 (Bup@N₂₀C) showing the best therapeutic effect. In vitro toxicity assessments showed high cell viability for all formulations, with Bup@N₂₀C showing the highest viability. Hemocompatibility tests showed less than 2% hemolysis, indicating good compatibility. Toxicity assessments in zebrafish embryos showed minimal developmental toxicity for Bup@N₂₀C. The study highlights the potential of niosomal Bup as a promising delivery system for MDD treatment.Niosomal Bupropion: Exploring Therapeutic Frontiers through Behavioral Profiling Bupropion (Bup) is a norepinephrine–dopamine reuptake inhibitor (NDRI) and the only FDA-approved drug of its class for treating major depressive disorder (MDD), sold as Wellbutrin. While effective, regular use and overdose can lead to seizures and liver failure. To improve efficacy and reduce dosing, this study nanoformulated Bup into niosomal vesicles. The thin film hydration method was used to synthesize and optimize Bup-loaded niosomes with three surfactants (Span 20, 40, 60) and cholesterol. The optimal niosome formulation was found to have a cholesterol-to-surfactant ratio of 1:1.5, with Bup@N₂O (Span 20) showing minimal toxicity and sustained Bup release in artificial cerebrospinal fluid (ACSF). The Bup@N₂O formulation improved exploration activity and reduced irregular movements in reserpine-induced depression in adult zebrafish, indicating potential for mood improvement. It outperformed the positive control group and was comparable to the control group, suggesting niosomal Bup as a promising delivery system for brain delivery by bypassing the blood-brain barrier. The study focused on optimizing cholesterol and surfactant concentrations for niosome stability and drug encapsulation. The optimal cholesterol concentration was 1 μM, and the optimal surfactant concentration was 1.5 μM. FTIR analysis confirmed niosome formation and Bup encapsulation. Stability studies showed minimal changes in vesicle size and PDI over 28 days. Scanning electron microscopy revealed spherical morphology with a size of 62 nm for Bup@N₂₀C. Bup release in ACSF showed sustained release, indicating enhanced therapeutic index. Behavioral analysis of adult zebrafish showed improved activity in the study groups, with NF1 (Bup@N₂₀C) showing the best therapeutic effect. In vitro toxicity assessments showed high cell viability for all formulations, with Bup@N₂₀C showing the highest viability. Hemocompatibility tests showed less than 2% hemolysis, indicating good compatibility. Toxicity assessments in zebrafish embryos showed minimal developmental toxicity for Bup@N₂₀C. The study highlights the potential of niosomal Bup as a promising delivery system for MDD treatment.