Homologous oridonin-loaded plant extracellular vesicles ameliorate metabolic-associated fatty liver disease by regulating lipid metabolism via the PPARγ/NLRP3-related pathway.

Metabolic-associated fatty liver disease (MAFLD) has become the leading chronic liver disease globally, with approximately one-third of individuals affected, yet there are currently no effective treatments available. Oridonin (ORI) is an active compound derived from the traditional Chinese herb Rabdosia rubescens, which exhibits anti-inflammatory effects and inhibits hepatic steatosis. Herb Rabdosia rubescens-derived extracellular vesicles (HREVs) have been shown to exert effects similar to those of ORI. In this study, we constructed homologous ORI-loaded plant HREVs (ORI/HREVs) to investigate their effects and underlying mechanisms on MAFLD. We successfully isolated HREVs, which exhibited characteristic cell-like morphology. Furthermore, HREVs were efficiently taken up by hepatic cells and RAW264.7 cells, primarily accumulated in the liver following intravenous injection and oral administration. In vivo, ORI/HREVs alleviated dyslipidemia, hyperglycemia, insulin resistance, and obesity in high-fat diet (HFD) mice with MAFLD. Histopathology confirmed that ORI/HREVs improved hepatic fat vacuoles, lipid droplet deposition, and inflammatory cell infiltration. ORI/HREVs alleviated hepatic cell injury in HFD-fed mice and cells stimulated with BSA-OA via suppressing oxidative stress and lipid accumulation, and promoting M2 polarization of macrophages. Mechanistically, the amelioration of hepatic steatosis upon ORI/HREVs treatment was correlated with lipid metabolism modulated by elevated PPARγ and suppressed NLRP3. In summary, this study revealed that ORI/HREVs exerted antioxidant and anti-inflammatory effects associated with modulation of the PPARγ/NLRP3 pathway, thereby suppressing de novo lipogenesis and alleviating MAFLD. More importantly, this study further confirmed that homologous ORI-loaded plant extracellular vesicles (ORI/HREVs) presented a promising strategy for the prevention and alleviation of MAFLD.