Fusion exosomes improve the antitumor effect of sorafenib by reversing tumor cell stemness

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly malignancies due to its aggressive nature, poor prognosis and lack of targeted treatment. Sorafenib is a clinical first-line multi-targeted tyrosine kinase inhibitor (TKI) drug for advanced HCC, but its responsiveness limits its long-term utility. Tumor stemness and epithelial-mesenchymal transition (EMT) contribute to TKI drug sensitivity. Sox4 can promote tumor resistance by endowing cancer cells with stemness and invasive properties. Therefore, reversing tumor stemness gene expression and improving tumor malignant phenotype is a promising strategy to increase the sensitivity of HCC to sorafenib. Here, we constructed a functional nanoplatform LE-T@SOR/shSox4 combines gene therapy with targeted therapy, and selectively delivers sorafenib and knockdown plasmid to tumor site. In vitro experiments demonstrate that LE-T@SOR/shSox4 can effectively inhibit the expression of stemness-related genes, reverse the EMT process and promote differentiation in HCC, thereby increasing the drug sensitivity of HCC to sorafenib. Compared with the control groups, administration of LE-T@SOR/shSox4 dramatically suppressed CD133 expression, reduced the tumor size, and effectively improved the antitumor effect of sorafenib in vivo . In conclusion, our study provides an effective therapeutic strategy for the clinical treatment of HCC.