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.
Major depressive disorder (MDD) is the most prevalent psychiatric disorder worldwide and severely limits psychosocial function and quality of life, but no effective medication is currently available. Circular RNAs (circRNAs) have been revealed to participate in the MDD pathological process. Targeted delivery of circRNAs without blood-brain barrier (BBB) restriction for remission of MDD represents a promising approach for antidepressant therapy. In this study, RVG-circDYM-extracellular vesicles (RVG-circDYM-EVs) were engineered to target and preferentially transfer circDYM to the brain, and the effect on the pathological process in a chronic unpredictable stress (CUS) mouse model of depression was investigated. The results showed that RVG-circDYM-EVs were successfully purified by ultracentrifugation from overexpressed circDYM HEK 293T cells, and the characterization of RVG-circDYM-EVs was successfully demonstrated in terms of size, morphology and specific markers. Beyond demonstrating proof-of-concept for an RNA drug delivery technology, we observed that systemic administration of RVG-circDYM-EVs efficiently delivered circDYM to the brain, and alleviated CUS-induced depressive-like behaviours, and we discovered that RVG-circDYM-EVs notably inhibited microglial activation, BBB leakiness and peripheral immune cells infiltration, and attenuated astrocyte disfunction induced by CUS. CircDYM can bind mechanistically to the transcription factor TAF1 (TATA-box binding protein associated factor 1), resulting in the decreased expression of its downstream target genes with consequently suppressed neuroinflammation. Taken together, our findings suggest that extracellular vesicle-mediated delivery of circDYM is effective for MDD treatment and promising for clinical applications.
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