Oleanolic Acid-Loaded Cyclodextrin Metal–Organic Framework Ameliorates NAFLD via Modulation of Gut Microbiota and Liver Metabolism

Oleanolic acid (OA) possesses hepatoprotective properties, but its clinical application is hampered by poor aqueous solubility. This study aimed to enhance OA solubility and investigate its therapeutic mechanism for NAFLD by encapsulating it in a γ-cyclodextrin metal–organic framework (OA@CDMOF). The OA@CDMOF complex was synthesized and characterized. Its effects on a high-fat diet (HFD)-induced NAFLD mouse model (MOD) were evaluated by combined liver metabolomics and 16S rRNA amplicon sequencing analyses. When encapsulated into CDMOF to yield an OA@CDMOF complex, the solubility of OA significantly improved. OA@CDMOF administration ameliorated HFD-induced metabolic alterations and liver injury. It modulated the gut microbiota composition, notably enriching the phylum Firmicutes while decreasing the abundance of Bacteroidota. Liver metabolomic analysis revealed that OA@CDMOF was associated with changes in metabolites related to glycerophospholipid, purine, glutathione, and vitamin B6 metabolism. Furthermore, it was associated with changes in metabolites related to lipolysis in adipocytes, pentose and glucuronate interconversions, and key signaling pathways, including AMPK, FoxO, and cGMP-PKG. Importantly, OA@CDMOF showed protective effects comparable to those of free OA, with no statistically significant difference between the two groups. This study elucidates the mechanism by which OA@CDMOF alleviates NAFLD through modulation of the gut microbiome and host metabolism. Our findings provide novel insights into the hepatoprotective role of OA@CDMOF and suggest a promising nanostrategy for NAFLD intervention.