Hepatocellular carcinoma (HCC) is the 5th most common cancer type and one of the most aggressive tumors with poor recovery rates. Sorafenib (SOR) is a potent multiple kinase inhibitor drug assigned by FDA as the drug of choice for resistant HCC. Midkine (MK) is a heparin-binding cytokine known to be overexpressed in several malignant tumors with mitogenic, angiogenic, anti-apoptotic and chemo-resistant functions. The aim of the current study was to design a nano-sized lipid-based co-delivery system encapsulating both SOR and a small interfering RNA (siRNA) against MK gene to create a synergistic formulation for maximal efficacy. Various lipids were screened and the highest efficiency was obtained with YSK05, a novel pH-sensitive lipid synthesized in our laboratory. Cell viability studies confirmed synergism between SOR and MK-siRNA with efficient gene silencing as demonstrated by quantitative real time polymerase chain reaction (qRT-PCR) studies. Optimization of different formulation variables created an efficient system with minimum carrier’s toxicity. To improve system’s specificity towards HCC, the system was decorated with a novel targeting ligand exclusive for HCC, namely SP94 peptide, and further optimization has been carried out to balance efficiency and specificity. The system was tested on HCC cell line, HepG2, versus normal hepatocytes, FL83B. Cellular uptake studies by flow cytometry indicated a significant difference between HCC and normal hepatocytes in the uptake of the optimized system proving system’s selectivity for HCC. Cell viability data confirmed the high efficiency and specificity of the optimized system in HCC cells with a minimum effect on normal hepatocytes. The current data are promising and will be extrapolated to the in vivo level in the future.