ROS/pH-Responsive Phenylboronic Acid-Chitosan Nanoparticles Improve Silymarin-Mediated Hepatoprotection After Hepatectomy With Gut-Liver Axis-Associated Responses.

To improve hepatoprotective delivery after hepatectomy, a ROS- and pH-responsive silymarin nanoplatform was constructed using phenylboronic acid-grafted chitosan (Sil@PBACS Nps). The nanoparticles displayed a uniform size of 250-300 nm, high encapsulation efficiency, and favorable colloidal stability. Their release behavior was accelerated under acidic and ROS-enriched conditions, supporting lesion-responsive silymarin delivery. Compared with free silymarin, Sil@PBACS Nps (Nps) exhibited stronger antioxidant activity, with DPPH and ABTS scavenging rates of 92.31% and 73.78%, respectively, together with moderate antibacterial effects against S. aureus and E. coli. The formulation showed good biocompatibility, with hemolysis below 5% and cell viability above 80% in AML-12 and HepG2 cells. In a canine hepatectomy model, oral Sil@PBACS Nps reshaped gut microbial composition and altered fecal metabolites associated with sphingolipid metabolism and the pentose phosphate pathway, while hepatic proteomics indicated pathway-level changes related to oxidative phosphorylation and fatty acid biosynthesis. Further validation of the targeted proteins in the mouse model confirmed the involvement of intestinal barrier-related responses in the mouse model and hepatic inflammatory, bile acid, antioxidant, lipid-metabolic, and apoptosis/recovery-associated pathways in both murine liver tissues. These results suggest that Sil@PBACS Nps facilitate post-hepatectomy liver recovery by integrating stimuli-responsive delivery, redox regulation, and gut-liver axis-associated hepatic protection.