The expression efficiency in liver following hydrodynamic delivery of in vitro transcribed mRNA was improved 2000-fold using a codon-optimized mRNA luciferase construct with flanking 3' and 5' human β-globin untranslated regions (UTR mRNA) over an un-optimized mRNA without β-globin UTRs. Nanoparticle UTR mRNA polyplexes were formed using a novel polyacridine PEG-peptide, resulting in an additional 15-fold increase in expression efficiency in the liver. The combined increase in expression for UTR mRNA PEG-peptide polyplexes was 3500-fold over mRNA lacking UTRs and PEG-peptide. The expression efficiency of UTR mRNA polyplex was 10-fold greater than the expression from an equivalent 1 μg dose of pGL3. Maximal expression was maintained from 4-24 h. Serum incubation established the unique ability of the polyacridine PEG-peptide to protect UTR mRNA polyplexes from RNase metabolism by binding to double stranded regions. UTR mRNA PEG-peptide polyplexes are efficient non-viral vectors that circumvent the need for nuclear uptake, representing an advancement toward the development of a targeted gene delivery system to transfect liver hepatocytes.Gene Therapy accepted article preview online, 30 June 2015. doi:10.1038/gt.2015.68.