Abstract / Summary
ABSTRACT 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.