Multifunctional membrane-core nanoparticles, composed of calcium phosphate cores, arginine-rich peptides, cationic and PEGylated lipid membranes, and galactose targeting ligands, have been developed as synthetic vectors for efficient nuclear delivery of plasmid DNA and subsequent gene expression in hepatocytes in vivo. Targeted particles exhibited rapid and extensive hepatic accumulation and were predominantly internalized by hepatocytes, while the inclusion of such peptides in LCP was sufficient to elicit high degrees of nuclear translocation of plasmid DNA. Monocyclic CR8C significantly enhanced in vivo gene expression over 10-fold more than linear CR8C, likely due to a release-favoring mechanism of the DNA/peptide complex. Though 100-fold lower in activity than that achieved via hydrodynamic injection, this formulation presents as a much less invasive alternative. To our knowledge, this is the most effective synthetic vector for liver gene transfer.