Background:　Sorafenib　is　approved　as　a　standard　therapy　for　advanced　hepatocellular　carcinoma　(HCC),　but　its　clinical　application　is　limited　due　to　moderate　therapeutic　efficacy　and　high　incidence　of　acquired　resistance　resulted　from　elevated　levels　of　SDF-1/CXCR4　axis　induced　by　prolonged　sorafenib　treatment.　We　previously　demonstrated　metapristone　(RU486　metabolite)　as　a　cancer　metastatic　chemopreventive　agent　targeting　SDF-1/CXCR4　axis.　Therefore,　we　hypothesized　that　combining　sorafenib　with　metapristone　could　synergistically　suppress　cell　proliferation,　enhance　anti-cancer　activity　and　repress　potential　drug　resistance.　Methods:　Changes　in　cellular　CXCR4　expression　by　metapristone　were　analyzed　by　RT-PCR　and　western　blotting.　Effect　of　combining　sorafenib　with　metapristone　on　cell　viability　was　examined　by　MTT　assay;　combination　index　value　was　calculated　to　evaluate　the　synergistic　effect　of　combined　therapy.　To　overcome　poor　pharmacokinetics　and　reduce　off-target　toxicity,　CXCR4-targeted　nanoparticles　(NPs)　were　developed　to　co-deliver　sorafenib　and　metapristone　into　CXCR4-expressing　HCC　in　vitro　and　in　vivo;　cell　proliferation,　colony　formation　and　apoptosis　assays　were　conducted;　nude　mice　bearing　HCC　xenograft　were　used　to　examine　effects　of　this　therapeutic　approach　on　HCC　progression.　Results:　Here　we　showed　metapristone　significantly　reduced　CXCR4　expression　in　HCC.　Combinatory　chemotherapy　of　sorafenib　with　metapristone　synergistically　suppressed　HCC　proliferation　and　resistance.　CXCR4-targeted　PEGylated　poly　(lactic-co-glycolic　acid)　NPs　conjugated　with　LFC131　(a　peptide　inhibitor　of　CXCR4),　could　deliver　more　sorafenib　and　metapristone　into　HCC　via　specific　recognition　and　binding　with　transmembrane　CXCR4,　and　resulted　in　the　enhanced　cytotoxicity,　colony　inhibition　and　apoptosis　by　regulating　more　Akt/ERK/p38　MAPK/caspase　signaling　pathways.　Co-delivery　of　sorafenib　with　metapristone　by　the　LFC131-conjugated　NPs　showed　prolonged　circulation　and　target　accumulation　at　tumor　sites,　and　thus　suppressed　tumor　growth　in　a　tumor　xenograft　model.　Conclusions:　In　conclusion,　co-delivery　of　sorafenib　and　metapristone　via　the　CXCR4-targeted　NPs　displays　a　synergistic　therapy　against　HCC.　Our　results　suggest　combinational　treatment　of　chemotherapeutics　offer　an　effective　strategy　for　enhancing　the　therapeutic　efficacy　on　carcinoma,　and　highlight　the　potential　application　of　ligand-modified　tumor-targeting　nanocarriers　in　delivering　drugs　as　a　promising　cancer　therapeutic　approach.　©　2019　The　Author(s).