Oral Plant‐Derived Nanomedicines Mitigate Acetaminophen‐Induced Liver Injury by Modulating the Gut‐Liver Axis and Intestinal Microbiota Metabolism

Abstract Excessive use of acetaminophen (APAP) can lead to drug‐induced liver injury, with its severity influenced by gut microbiota and their metabolites. The gut‐liver axis, a complex bidirectional communication system between the gut and liver, plays a crucial role in maintaining overall health. Here, an innovative oral drug delivery system is developed based on DSPE‐PEG2000‐modified mulberry leaf‐derived exosome‐like nanoparticles loaded with silymarin nanocrystals (PEG@SN‐MNs). In vitro, experiments reveal that PEG@SN‐MNs protected HepG2 cells from APAP‐induced damage by mitigating oxidative stress and exhibit notable anti‐inflammatory and antioxidant effects in lipopolysaccharide‐stimulated Raw 264.7 macrophages. While intravenous administration of various nanoparticles induces obvious adverse effects, oral delivery exhibits excellent in vivo safety. In an APAP‐induced liver injury mice model, oral PEG@SN‐MNs successfully traverse the gastrointestinal tract, are absorbed into the bloodstream via vascular endothelial cells, target the liver, and are selectively internalized by hepatocytes and macrophages through galactose receptors. Furthermore, PEG@SN‐MNs rebalance gut microbiota homeostasis and regulate lipid and tryptophan metabolism, thereby alleviating APAP‐induced liver injury through modulation of the gut‐liver axis. These findings highlight PEG@SN‐MNs as a promising oral therapeutic platform for the treatment of APAP‐induced liver injury.