Dual-ligand-modified cantharidin nanoparticles for the treatment of hepatocellular carcinoma via the inhibition of Ephb4

, and 43.2% apoptosis in Huh-7 cells. Mechanistically, GA-FA-CSLNs downregulated Eph receptor B4(EphB4) and Bcl-2, while upregulating caspase-3 and Bax. In vivo, the tumor inhibition rate reached 58.67%, superior to free CTD and sorafenib, with 100% 14-day survival and no significant abnormalities in serum biochemistry or histopathology. Pharmacokinetic analysis showed prolonged elimination half-life (2.54 h) and a 3.2-fold increase in area under the blood concentration-time curve versus unmodified CSLNs. GA-FA-CSLNs represent a promising actively targeted nanoplatform that enhances CTD antitumor efficacy against HCC via EphB4 pathway inhibition while reducing systemic toxicity, offering a potential strategy for targeted HCC therapy.