Due to its efficient and specific gene silencing ability, RNA interference has shown great potential in the treatment of liver diseases. However, achieving in vivo delivery of siRNA to critical liver cells remains the biggest obstacle for this technique to be a real clinical therapeutic modality. In this study, we describe a promising liver targeting siRNA delivery system based on N-acetylgalactosamine functionalized mixedmicellar nanoparticles (Gal-MNPs), which can efficiently deliver siRNA to hepatocytes and silence the target gene expression after systemic administration. The Gal-MNPs were assembled in aqueous solution from mixed N-acetylgalactosamine functionalized poly(ethylene glycol)-bpoly(ε-caprolactone) and cationic poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) (PCL-b-PPEEA); the properties of nanoparticles, including particle size, zeta potential and the density of poly(ethylene glycol) could be easily regulated. The hepatocyte-targeting effect of Gal-MNP was demonstrated by significant enrichment of fluorescent siRNA in primary hepatocytes in vitro and in vivo. Successful down-regulation of liver-specific apolipoproteinB (apoB) expression was achieved in mouse liver, at both the transcriptional and translational level, following intravenous injection of Gal-MNP/siapoB to BALB/c mice. Systemic delivery of Gal-MNP/siRNA did not induce the innate immune response or positive hepatotoxicity. The results of this study suggest therapeutic potential for the Gal-MNP/siRNA system in liver diseases.