Liver cells-derived extracellular vesicles deliver a dual-functional RNA ligand for TACE treatment of hepatocellular carcinoma.

Current chemotherapeutic agents, such as doxorubicin (DOX), in transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) encounter resistance and limited effects, attenuating TACE efficacy in patients with unresectable and residual HCC. To address these issues, we developed a 5' triphosphorylated oligonucleotide (imm-miR223) with dual function as miR-223 analogue and RIG-I activation, and delivered this RNA molecule to HCC cells efficiently using normal hepatic cell-derived extracellular vesicles (EVs). These imm-miR223-EVs reversed DOX resistance, suppressed HCC cell proliferation and migration via targeting FOXO3a, and induced immune responses by activating RIG-I cascade, thereby significantly inhibiting the growth of HCC in vitro and in vivo, especially when combined with DOX. The use of homologous EVs delivering a dual-functional stem-loop RNA, which concurrently reverses chemoresistance and activates innate immune receptor signaling, may offer a more effective therapeutic strategy for HCC.