Therapeutic Delivery of circDYM by Perillyl Alcohol Nanoemulsion Alleviates LPS‐Induced Depressive‐Like Behaviors

Abstract RNA therapeutics have recently shown significant promise in treating a variety of diseases, including cancers, infectious diseases, and genetic disorders. However, their potential in addressing neuropsychiatric disorders has been limited by the lack of an efficient delivery system to the central nervous system (CNS). Here, a novel nanoemulsion platform, perillyl alcohol nanoemulsions (PANEs) is introduced, designed for the therapeutic delivery of circDYM to brain and alleviated depressive‐like behaviors. PANEs successfully encapsulated circDYM using cationic lipid compositions, enhancing its delivery efficiency to the mouse brain via its perillyl alcohol phase. The optimized formulation, PANE2‐4, significantly improved the brain delivery efficiency of circDYM compared to both free circDYM and standard lipid nanoparticle formulations. Intranasal administration of PANE2‐4‐circDYM effectively alleviated depressive‐like behaviors in the LPS‐induced mouse model of depression. This effect is achieved by reducing the CD11b⁺CD45^dim microglia population and iNOS expression, restoring the expression of protein‐95 (PSD‐95) and synaptophysin. These findings indicated that PANE represents an efficient platform for delivering circRNAs to the brain, and intranasal administration of PANE2‐4‐circDYM is a promising strategy for ameliorating LPS‐induced depressive‐like behaviors.