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.
Acute liver failure (ALF) is a severe life-threatening disease associated with the disorder of the gut-liver axis. However, the cellular characteristics of ALF in the gut and related therapeutic targets remain unexplored. Here, we utilized the D-GALN/LPS (D/L)-induced ALF model to characterize 33,216 single-cell transcriptomes and define a mouse ALF intestinal cellular atlas. We found that unique, previously uncharacterized intestinal immune cells, including T cells, B cells, macrophages, and neutrophils, are responsive to ALF, and we identified the transcriptional profiles of these subsets during ALF. We also delineated the heterogeneity of intestinal epithelial cells (IECs) and found that ALF-induced cell cycle arrest in intestinal stem cells and activated specific enterocyte and goblet cell clusters. Notably, the most significantly altered IECs, including enterocytes, intestinal stem cells and goblet cells, had similar activation patterns closely associated with inflammation from intestinal immune activation. Furthermore, our results unveiled a common Ep300 -dependent transcriptional program that coordinates IEC activation during ALF, which was confirmed to be universal in different ALF models. Pharmacological inhibition of Ep300 with an inhibitor (SGC-CBP30) inhibited this cell-specific program, confirming that Ep300 is an effective target for alleviating ALF. Mechanistically, Ep300 inhibition restrained inflammation and oxidative stress in the dysregulated cluster of IECs through the P38-JNK pathway and corrected intestinal ecology by regulating intestinal microbial composition and metabolism, thereby protecting IECs and attenuating ALF. These findings confirm that Ep300 is a novel therapeutic target in ALF and pave the way for future pathophysiological studies on ALF.
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