Biohybrid nanovesicle-mediated targeted delivery of HSP90 inhibitor for enhanced sorafenib therapy of hepatocellular carcinoma after radiofrequency ablation

Abstract

Hepatocellular carcinoma (HCC) presents significant therapeutic challenges due to enhanced liver cancer stem cell (LCSC) stemness and sorafenib resistance after radiofrequency ablation (RFA). To address these limitations, biohybrid nanovesicles (hNVs) are prepared by fusing milk-derived exosomes with sorafenib-resistant LM3 cell membranes as nanovectors for targeted delivery of the HSP90 inhibitor alvespimycin (17-DMAG). The hNVs exhibit enhanced tumor-homing capability through homologous targeting, achieving 3.2-fold higher tumor accumulation compared to unmodified exosomes. RFA of HCC significantly upregulates the expression of HSP90, leading to enhanced LCSC stemness and sorafenib resistance. In vitro and in vivo studies demonstrate that 17-DMAG loaded hNVs (17-DMAG@hNVs) effectively suppress LCSC stemness by downregulating HSP90 and its downstream signal pathways (TGF-β/Smad3 and JAK/STAT3), thereby restoring sorafenib sensitivity. Therefore, 17-DMAG@hNVs remarkably enhance the therapeutic efficacy of sorafenib after RFA of HCC. The reversal of LCSC stemness by inhibiting HSP90 expression using 17-DMAG@hNVs provides a promising approach to overcome sorafenib resistance for enhanced therapy of HCC after RFA.