Intranasal Delivery of Hydrophobic AC5216 Loaded Nanoemulsion into Brain To Alleviate Chronic Unpredictable Stress-Induced Depressive-like Behaviors

Major depressive disorder (MDD) represents a widespread mental health condition. Efficiently moving therapeutic substances across the blood–brain barrier (BBB) remains a critical obstacle in addressing depressive disorders. AC5216, identified as a translocator protein (TSPO) ligand and considered a potential treatment for major depressive disorder (MDD), faces limitations due to its subpar druggability and oral bioavailability. In this context, an amphiphilic polymer composed of polyethylene glycol, poly- l -lysine, and poly(lactic- co -glycolic acid) (PEG-PLL-PLGA) has been utilized to encapsulate the hydrophobic compound AC5216. This results in the formation of cell-penetrating peptide-modified nanoemulsions (termed CPP-PPP-AC5216), designed to deliver AC5216 directly into the central nervous system via intranasal administration for MDD therapy. Research on animal models has shown that CPP-PPP-AC5216 effectively transports AC5216 to the brain, significantly mitigating chronic unpredictable stress (CUS)-induced depressive behaviors with a dosage as low as 0.03 mg/kg when administered intranasally. Furthermore, it was observed that CPP-PPP-AC5216 substantially reduces microglial activation, prevents BBB leakage, and ameliorates astrocyte dysfunction caused by CUS. The findings suggest a promising potential for using this nanoemulsion approach to deliver hydrophobic compounds through the nasal route for the treatment of MDD.