Hepatocellular carcinoma (HCC) is one of the main causes of cancer death worldwide. Thus, the main objective of this work was to develop a new targeted lipid-polymer hybrid nanosystem that could allow the simultaneous transport of different therapeutic agents, namely antitumor drugs and nucleic acids, and their specific delivery in HCC cells. This formulation has the capability to mediate combined chemotherapy and gene therapy, as it efficiently loaded and delivered, in target cells, the drugs selumetinib and perifosine, and the PTEN transgene.