Preventive effects and mechanisms of yam exosome-like nanoparticles on acute liver injury.

Acute liver injury (ALI) represented a significant clinical challenge due to its high mortality rate and the absence of specific therapeutic interventions. Plant-derived exosome-like nanoparticles (ELNs) had recently garnered increasing attention in the field of disease prevention and treatment, owing to their favorable biocompatibility and potential for targeted delivery. In this study, we isolated and systematically characterized ELNs from the medicinal plant yam (Yam ELNs). Structural analysis revealed that Yam ELNs possess a homogeneous bilayer membrane structure with an average particle size of 214.7 nm and demonstrated considerable stability in gastrointestinal fluids. These nanoparticles were found to be enriched with lipids (primarily phosphatidylcholine, PC), functional proteins (including GPX1 and GSTP1), and microRNAs (such as the miR159 family). In vivo imaging and cellular uptake assays indicated that Yam ELNs were efficiently internalized by the liver and HepG2 cells. Using a carbon tetrachloride (CCl₄)-induced ALI model, we demonstrated that oral administration of Yam ELNs significantly reduced serum markers of liver injury (ALT and AST), ameliorated oxidative stress imbalance (as evidenced by decreased MDA and increased GSH levels), and attenuated histopathological damage in the liver. Furthermore, in vitro experiments confirmed that Yam ELNs modulate cellular oxidative stress through their cargo of endogenous functional RNA molecules, thereby exerting a prophylactic protective effect. Desorption electrospray ionization mass spectrometry imaging (DESI-MSI) visually demonstrated that Yam ELNs remodel the spatial distribution of glycerophospholipid metabolism and suppress lipid peroxidation and the propagation of inflammation. Targeted lipidomics analysis further revealed that disturbances in several core metabolic pathways, including glycerophospholipid metabolism and linoleic acid metabolism, were corrected by Yam ELNs. As a result, the homeostasis of key phospholipid species, such as PE, PI, and PS, was maintained, and the propagation of inflammatory responses was limited. Notably, Yam ELNs pretreatment significantly reduced serum levels of lipopolysaccharide (LPS) and downregulated hepatic Toll-like receptor 4 (TLR4) expression, indicating preservation of intestinal barrier integrity and attenuation of endotoxin-triggered hepatic inflammation. Furthermore, an integrated correlation analysis based on gut microbiota 16S rRNA sequencing, fecal metabolomics, and untargeted serum metabolomics clarified the relationships between differential serum metabolites, fecal metabolites, and microbial community structure. Following treatment with Yam ELNs, modulation of gut microbiota composition was observed, marked by the enrichment of Lactobacillus spp. These microbial shifts correlated with concurrent improvements in both serum lipid profiles and fecal metabolite profiles. Collectively, these effects were associated with enhanced hepatoprotective efficacy, suggesting a gut-initiated and metabolism-mediated mechanism underlying the prophylactic protection against ALI. In summary, this study systematically establishes the substantial potential of Yam ELNs in the prevention and treatment of liver injury, offering a novel strategy for the development of natural vesicle-based liver-targeted therapies.