Abstract: Objective To investigate the effect of extracellular vesicle loaded with lenvatinib on the proliferation, invasion and apoptosis of hepatocellular carcinoma cell line HepG2. 
Methods Liver cancer cell line HepG2 group, extracellular vesicles group (EVs suspension 5 mL, 106/mL), lenvatinib group (lenvatinib 5 mL, 30 mg/L), and lenvatinib-loaded vesicle group (EVs suspension 5 mL, 106/mL+lenvatinib 5 mL, 30 mg/L). Six parallel samples were set up in each well of the above groups and cultured for 72 h. Cell proliferation, invasion, migration and apoptosis were measured after the end of culture. The expression levels of miR-482 and CYR61 in each group were detected by real-time PCR (RT-PCR) and Western blot. 
Results Compared with HepG2 group, the OD value, survival rate, the number of monoclonal clones formed, the number of transmembrane cells, the migration distance, the apoptosis rate, the mRNA and protein levels of miR-482 and CYR61 in the extracellular vesicle group had no significant changes (P＞0.05). Compared with the HepG2 group and the extracellular vesicle group, OD value, survival rate, number of monoclonal clones formed, number of transmembrane cells, migration distance, CYR61 mRNA and protein levels were decreased in the lenvatinib group and the lenvatinib-loaded vesicle group, while apoptosis rate and miR-482 were increased (P＜0.05). Compared with the lenvatinib group, the OD value, survival rate, the number of monoclonal clones formed, the number of transmembrane cells, the migration distance, CYR61 mRNA and protein levels were decreased in the lenvatinib-loaded vesicle group, while the apoptosis rate and miR-482 were increased (P＜0.05). 
Conclusion Extracellular vesicles loaded with lenvatinib can significantly enhance the killing effect of chemotherapy lenvatinib on hepatocellular carcinoma cell line HepG2, and increase its inhibitory effect on proliferation, invasion and pro-apoptosis. The mechanism may be related to the increased expression of miR-482 and decreased expression of CYR61 in HepG2 cells loaded with lenvatinib in extracellular vesicles. 

Key words: carcinoma, hepatocellular, extracellular vesicles, lenvatinib