Sorafenib is one of the few effective first-line drugs approved for the treatment of advanced
hepatocellular carcinoma (HCC). However, the development of drug resistance is common among individuals with HCC. Recent evidence indicated that the anticancer activity of
sorafenib mainly relies on the induction of ferroptosis. Furthermore, in our study, genes that suppress ferroptosis, especially GPX4 and
DHODH, were enriched in
sorafenib-resistant cells and primary tissues and were associated with poor prognosis of HCC patients who received
sorafenib treatment. Therefore, a new ferroptosis inducer comprising a multiplex
small interfering RNA (multi-
siRNA) capable of simultaneously silencing GPX4 and
DHODH was created. Then, exosomes with high multi-
siRNA loading and HCC-specific targeting were established by fusing the SP94
peptide and the N-terminal RNA recognition motif (RRM) of U1-A with the exosomal
membrane protein Lamp2b. The results from the in vitro and in vivo experiments indicate that this
tumor-targeting
nano-delivery system (ExoSP94-lamp2b-RRM-multi-siRNA) could enhance
sorafenib-induced ferroptosis and overcome
sorafenib resistance. Taken together, HCC-targeted exosomes (ExoSP94-Lamp2b-RRM) could specifically deliver multi-
siRNA to HCC tissues, enhance
sorafenib-induced ferroptosis by silencing GPX4 and
DHODH expression and consequently increase HCC sensitivity to
sorafenib, which opens a new avenue for clinically overcoming
sorafenib resistance from the perspective of ferroptosis.