Intranasal Delivery of circATF7IP siRNA via Lipid Nanoparticles Alleviates LPS-induced Depressive-Like Behaviors

Major depressive disorder (MDD) is a prevalent mental disorder that significantly impacts social and psychological function, but no effective medication is currently available. Circular RNAs (circRNAs) have been reported to participate in the pathogenesis of MDD which are envisioned as promising therapeutic targets. However, nonviral-based delivery strategies targeting circRNA against MDD are not thoroughly investigated. Here, it is identified that circATF7IP is significantly upregulated in plasma samples and positively correlated with 24-Hamilton Depression Scale (HAMD-24) scores of MDD patients. Synergistic amine lipid nanoparticles (SALNPs) are designed to deliver siRNA targeting circATF7IP (si-circATF7IP) into the hippocampus brain region by intranasal administration. Intranasal delivery of SALNP-si-circATF7IP successfully alleviated the depressive-like behaviors in the LPS-induced mouse depression model via decreasing CD11b+CD45dim microglia population and pro-inflammatory cytokine productions (TNF-alpha and IL-6). These results indicate that the level of circATF7IP positively correlates with MDD pathogenesis, and SALNP delivery of si-circATF7IP via intranasal administration is an effective strategy to ameliorate LPS-induced depressive-like behaviors. CircATF7IP level is upregulated in MDD patients and positively correlated with the pathogenesis of MDD. SALNP-si-circATF7IP is designed to downregulate the level of circATF7IP in the brain. Intranasal delivery of SALNP-si-circATF7IP to mouse brains alleviated LPS-induced depression-like behaviors by inhibiting microglia activation as well as pro-inflammatory cytokine (TNF-alpha and IL-6) production. image