Taken together, reactivation of Akt and ERK signaling with sorafenib confirmed CD133+ Huh7 population contribute to resistance in sorafenib treatment and the sgIF loaded HLC9-EVs effectively annulled sorafenib resistance by interfering reactivation of PI3K/Akt and MAPK/ERK, the two important signaling pathways actively involved in cancer progression. This evidence concerns the gene PROM1 and cancer.