Hepatic stellate cells (HSCs), as an important part of the tumor microenvironment (TME), could be activated by tumor cells as cancer-associated fibroblasts (CAFs), thereby promoting the production of extracellular matrix (ECM) and favoring the development of tumors. Therefore, blocking the "CAFs-ECM" axis is a promising pathway to improve antitumor efficacy. Based on this, we developed a multifunctional nanosized delivery system composed of hyaluronic acid-modified pH-sensitive liposomes (CTHLs) and glycyrrheic acid-modified nanomicelles (DGNs), which combines the advantages of targeted delivery, pH-sensitivity, and deep drug penetration. To mimic actual TME, a novel HSCs+BEL-7402 cocultured cell model and a m-HSCs+H22 coimplanted mice model were established. As expected, CTHLs and DGNs could target CAFs and tumor cells, respectively, and promote the drug penetration and retention in tumor regions. Notably, CTHLs+DGNs not only exhibited a superior antitumor effect in three-level tumor-bearing mice but also presented excellent antimetastasis efficiency in lung-metastatic mice. The antitumor mechanism revealed that the lipid&micelle mixed formulations effectively inhibited the activation of CAFs, reduced the deposition of ECM, and reversed the epithelial-mesenchymal transition (EMT) of tumor cells. In brief, the nanosized delivery system composed of CTHLs and DGNs could effectively improve the therapeutic effect of liver cancer by blocking the "CAFs-ECM" axis, which has a good clinical application prospect.
Keywords: combination therapy; hepatocellular carcinoma; nanosized delivery system; tumor microenvironment; tumor-targeting.