Hepatocellular carcinoma (HCC) is the worldwide's fifth cause of death. In the present study, we designed a novel lipid-based nanoplatform for highly-specific and efficient co-delivery of the cytotoxic drug, sorafenib (SOR), and small interfering RNA against Midkine gene (MK-siRNA) to HCC cells. SOR is designated by the FDA as the drug of choice for resistant HCC. Midkine (MK) is a growth cytokine highly-expressed in HCC with multiple malignant functions. The system was modified with a specific peptide ligand for selective uptake into HCC cells. We showed the first evidence that the combination of SOR and MK-siRNA had a synergistic cytotoxic effect on HCC cells. Our laboratory’s novel pH-sensitive cationic lipid, YSK05, showed the highest efficiency among the investigated lipids. Moreover, optimization of formulation variables improved the system’s outcome and resulted in a highly-specific internalization in both human and mouse HCC cells, (HepG2 and Hepa 1-6, respectively) compared to a significantly-lower internalization in other cancerous cells from non-HCC origin (HeLa), and no internalization in normal hepatocytes (FL83B). Cell viability studies confirmed the same highly-selective cytotoxicity pattern. The nanoplatform developed in this study has high potential as a promising therapy for HCC with minimum effect on normal cells.