Camel milk extracellular vesicles-mediated co-delivery of siVEGF/sorafenib enhances the anti-hepatocellular carcinoma activity by dual-effect blocking the biological effects of VEGF.

In view of the combined effect of paracrine and autocrine of VEGF in tumor tissues, this study proposed to use sorafenib to block VEGF signaling pathway, while siRNA was used to interfere with tumor cell autocrine of VEGF, so as to achieve double-effect blocking of VEGF biological effects and further improve anti-tumor efficacy. Here, we constructed a novel co-delivery system (so-cEVs-PPT/siVEGF) based on camel milk-derived extracellular vesicles (cEVs) modified by Plannic 123-polyethylenimine-tLyP-1 transmembrane peptide polymer (PPT) for the delivery of siVEGF and sorafenib. The results showed that so-cEVs-PPT/siVEGF exhibited significant tumor inhibition and low side effects on hepatocellular carcinoma mice, and the combined administration system had stronger anti-tumor effects than siVEGF or sorafenib alone. More importantly, the two different delivery modes of intravenous injection and intratumoral injection showed comparable anti-tumor therapeutic effects, which proved that the drug delivery system had superior targeted therapeutic effects. This study proposes an innovative combination therapy strategy that provides new perspectives and possibilities for the treatment of hepatocellular carcinoma.