Despite extensive investigations on siRNA delivery systems for the past decade, there has been no clinically available product until now. In this work, reducible hyaluronic acid (HA)–siRNA conjugate was successfully synthesized and used to make a complex with cationic solid lipid nanoparticles (CSLNs) for the development of a liver specific siRNA delivery system. The reducible HA–siRNA conjugate was synthesized by the disulfide–thiol exchange reaction between pyridyldithiol modified HA and thiolated siRNA. The remaining pyridyldithiol was further blocked with cysteine. The biomimetic CSLNs were prepared by reconstituting the composition of natural apolipoprotein-free low density lipoproteins (LDLs). The formation of the HA–siRNA/CSLN complex was confirmed by gel electrophoresis (GE), dynamic light scattering (DLS), and atomic force microscopy (AFM). The HA–siRNA/CSLN complex showed remarkably low cytotoxicity and high transfection efficiency in the presence of serum. The therapeutic index (LC₅₀/IC₅₀) of the HA–siRNA/CSLN complex was statistically much higher than that of a HA–siRNA conjugate or siRNA complexed with commercially available siRNA transfection reagents like in vivo jetPEI and INTERFERin, as well as an siRNA/CSLN complex. The HA–siRNA/CSLN complex can be effectively applied as a model system for the treatment of liver diseases, such as liver fibrosis and liver cancer.