A novel supramolecular nanoparticle system with core-shell structure was designed based on β-cyclodextrin-conjugated poly-l-lysine (PLCD) and hyaluronic acid for co-delivery of gene and chemotherapy agent targeting hepatocellular carcinoma (HCC). PLCD was synthesized by the conjugation of monoaldehyde activated β-cyclodextrin with poly-l-lysine via Shiff's base reaction. Doxorubicin, as a model therapeutic drug, was included into the hydrophobic cavity of β-cyclodextrin in PLCD through host-guest interaction. OligoRNA, as a model gene, was further condensed into the inclusion complexes by electrostatic interaction to form oligoRNA and doxorubicin co-loaded supramolecular nanoparticle system. Hyaluronic acid, which is often over-expressed by HCC cells, was coated on the surface of the above nanoparticles to construct HCC-targeted nanoparticle system. These nanoparticles had regular spherical shape with classic "core-shell" structure, and their size and zeta potential were 195.8nm and -22.7mV, respectively. The nanoparticles could effectively deliver doxorubicin and oligoRNA into HCC cells via CD44 receptor-mediated endocytosis and significantly inhibit the cell proliferation. In the nude mice bearing MHCC-97H tumor, the nanoparticles could be efficiently accumulated in the tumor, suggesting their strong hepatoma-targeting capability. These findings demonstrated that this novel supramolecular nanoparticle system had a promising potential for combining gene therapy and chemotherapy to treat HCC.