Epimedium-Derived Exosome-like Nanovesicles Regulate Lipid Metabolism via the “Gut–Kidney Axis” for Multitargeted Inhibition of Sepsis-Associated Acute Kidney Injury

Sepsis-associated acute kidney injury (S-AKI) is a major cause of acute kidney injury (AKI) in intensive care units, with persistently high incidence and mortality that pose significant clinical challenges. In this study, we isolated exosome-like nanovesicles (ENVs) from the traditional Chinese herb Epimedium sagittatum and evaluated their therapeutic potential in S-AKI. ENVs exhibited significant kidney-targeting ability and ameliorated renal injury in a murine S-AKI model. Mechanistically, ENVs reshaped the gut microbiota, promoted the production of short-chain fatty acids (SCFAs), and enhanced intestinal barrier function, thereby reducing systemic lipopolysaccharide (LPS) translocation and suppressing the TLR4/NF-κB pathway. Additionally, ENVs were enriched with bioactive lipids and flavonoids, which contributed to antioxidant and anti-inflammatory effects, including the downregulation of proinflammatory cytokines (TNF-α, IL-6, and IL-1β). Transcriptomic analysis revealed that ENVs modulated key genes and pathways involved in lipid metabolism and gut-kidney crosstalk. Our findings demonstrate for the first time that Epimedium-derived ENVs attenuate S-AKI through multitargeted mechanisms centered on the gut-kidney axis, offering a novel strategy for early clinical intervention.