An N-glycan targeted non-viral gene delivery system was developed to express proteins encoded in plasmid DNA nanoparticles. DNA was condensed into a nanoparticle of approximately 170 nm diameter by a unique PEGylated glycopeptide. The chemical synthesis of the PEGylated glycopeptide involved solid phase synthesis of an 18 amino acid polyacridine peptide containing a single Cys, multiple Lys and four Lys-Acr residues. The number and spacing of acridines (Acr) were essential to achieve tight binding to plasmid DNA through polyintercalation, resulting in DNA nanoparticles that are stable in the circulation. A triantennary N-glycan was purified from bovine fetuin and derivatized with a reducing-end tyrosinamide group. Bioconjugation of the triantennary N-glycan to 5 kDa PEG followed by attachment to the Cys of the polyacridine peptide completed the synthesis of the PEGylated glycopeptide DNA delivery system. I.V. administration of N-glycan targeted DNA nanoparticles resulted in uptake by the asialoglycoprotein receptor on hepatocytes in mice and transgene expression in the liver as determined by bioluminescence imaging of luciferase expression in the liver. The results demonstrate an approach to prepare stable N-glycan targeted DNA nanoparticles that function in mice.

Gene expression mediated by N-glycan targeted DNA nanoparticles

253rd National Meeting (2017)

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