Development and evaluation of exosome-encapsulated lenvatinib/h-BN nanocomposites for targeted chemo-photothermal therapy of hepatocellular carcinoma with enhanced pharmacokinetics

The development of multifunctional nanoplatforms for synergistic tumor treatment has attracted significant attention for their ability to minimize systemic toxicity while enhancing therapeutic efficacy. Herein, we fabricated a new nanocomposite by loading lenvatinib (LEN) onto hexagonal boron nitride (h-BN) and coating it with exosomes (EX) to form LEN-h-BN@EX for combined chemo-photothermal therapy (chemo-PTT) against hepatocellular carcinoma (HCC). In vitro cytotoxicity assays using HepG2 cells indicated significantly enhanced antitumor activity of LEN-h-BN@EX under near-infrared (NIR) irradiation (IC₅₀=132.2μg/mL). Pharmacokinetics analysis revealed significantly prolonged plasma retention and systemic exposure, with an extended half-life (12.3 h) and a markedly increased AUC_0-t (120µg·h/mL). TEM analysis indicated efficient endocytosis of h-BN and LEN-h-BN@EX NPs, demonstrating that NPs entered cells via endocytosis under NIR, further confirming their successful internalization. In vivo experiments in BALB/c mice revealed that the chemo-PTT achieved the most pronounced therapeutic effect, reducing tumor weight to 0.28 g and tumor volume to 249.7 mm³. Molecular dynamics results indicated that the protein-ligand LEN complex demonstrated high rigidity, as evidenced by a low backbone RMSD following equilibration, minimal residue fluctuations (RMSF) within the binding site, and stable values for both the Rg and SASA. Molecular Docking results revealed strong binding affinities (-7.2 to -7.9kcal/mol), with VEGFR3 showing the highest affinity through hydrogen bonding, electrostatic, and hydrophobic interactions. Overall, these results establish LEN-h-BN@EX as a potent and biocompatible nanoplatform that integrates targeted delivery, enhanced pharmacokinetics, and synergistic chemo-PTT activity, offering a promising strategy for safe and effective liver cancer treatment.