In non-viral gene delivery, vectors with high transfection efficiencies often suffer from high toxicities, making it unlikely to improve their efficiencies by increasing the dosage. In this study, we developed a ternary polyplex system which comprised of a membrane-active cationic helical polypeptide (PVBLG-8), a cationic helical polypeptide (PVBLG-7) capable of mannose receptor targeting, and a plasmid DNA (pDNA). The presence of PVBLG-7 moiety notably enhanced the cellular uptake and transfection efficiency of the polyplex in a variety of mannose receptor-expressing cells, such as HeLa, COS-7, and Raw 264.7, and showed limited effect on the membrane permeability of PVBLG-8 or overall cytotoxicity of the polyplex.  The self-assembly composition of the ternary polyplex could be readily tuned and the optimal formulations of the ternary complexes with a proper balance of the membrane activity and the targeting capability were easily identified in each specific cell type, which displayed desired cell tolerability and markedly outperformed the PVBLG-8/pDNA binary complexes and the commercial reagent Lipofectamine 2000 in terms of transfection efficiency. This study provides an effective and facile strategy to overcome the efficiency-toxicity inconsistency of non-viral vectors and strengthen their delivery efficiencies, providing insights into the design of effective and safe non-viral gene delivery vectors.

Maximizing gene delivery efficiencies of cationic helical polypeptides via optimized combination between membrane penetration and cellular targeting

246th National Meeting (2013)

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