Cell-liposome delivery system based on neuroinflammation to target the amygdala for ameliorating depressive-like behaviors

Depression is a serious psychiatric disorder with unsatisfactory outcomes due to difficulties in delivering therapeutic molecules from the periphery to the brain. Neuroinflammation plays a key role in neurobiology and the treatment of depression. Neutrophils can cross the blood-brain barrier (BBB) and infiltrate key brain regions related to the pathophysiology of depression during neuroinflammation. N-Acetyl Pro-Gly-Pro (PGP) peptides efficiently bind to CXCR2 receptors on the surface of neutrophils. The neuropeptide oxytocin demonstrated antidepressant properties in preclinical and clinical studies, but its inability to penetrate the BBB hampers its therapeutic applications. In this study, we established a novel drug delivery system based on neutrophil infiltration in key brain regions during neuroinflammation. PGP was used to modify oxytocin-loaded liposomes (PGP-OTL) as the target ligand. Systematic administration of PGP-OTL exhibited enhanced antidepressant properties resulting from elevated oxytocin concentrations, especially in the amygdala, a crucial depression-implicated brain region. Enhanced antidepressant effects of PGP-OTL, similar to the ones caused by central oxytocin infusion, were observed in behavioral measurement including forced swim and tail suspension tests. Our study demonstrated that PGP-OTL can "hitchhike" neutrophils and enhance delivery of therapeutics into the brain, thus providing the means for developing novel cell-liposome-based drug delivery strategies for depression therapy.