Engineering a Galactosylated Zein-Orientin Nanoplatform for NAFLD Alleviation via Lipid Metabolic Modulation and Gut Microbiota Remodeling

Abstract Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipid accumulation, and the existing pharmacological alternatives are constrained by considerable side effects and probable toxicity. Orientin (Ori), a natural flavonoid with hepatoprotective potential, is restricted by poor solubility and low bioavailability. Herein, a galactosylated zein nanoplatform (Ori@Gal-Zein) was engineered via the Maillard reaction, resulting in uniform spherical nanoparticles (163.3 ± 2.6 nm) with high loading capacity of Ori (7.89 ± 0.14%) and gastrointestinal stability. In a CDAHFD-induced NAFLD mouse model, Ori@Gal-Zein decreased hepatic triglyceride and total cholesterol accumulation, attenuated lipid peroxidation, and restored antioxidant capacity, exhibiting comparable efficacy to silybin. Moreover, lipidomics revealed decreased triglyceride, diglyceride, and ceramide levels and restored the phosphatidylcholine/phosphatidylethanolamine ratio. Importantly, Ori@Gal-Zein remodeled gut microbiota by normalizing the Firmicutes/Bacteroidetes ratio, decreasing Pseudomonadota proliferation, and increasing Akkermansia abundance to alleviate NAFLD, providing a selection for carbohydrate-mediated protein nanoplatform.