Rujing Zhang1, Nan Zheng1, Ziyuan Song1, Lichen Yin2, Jianjun Cheng3. 1. Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, 1304 W Green Street, Urbana, IL 61801, USA. 2. Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, 1304 W Green Street, Urbana, IL 61801, USA. Electronic address: lcyin@illinois.edu. 3. Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, 1304 W Green Street, Urbana, IL 61801, USA. Electronic address: jianjunc@illinois.edu.
Abstract
The rational design of effective and safe non-viral gene vectors is largely dependent on the understanding of the structure-property relationship. We herein report the design of a new series of cationic, α-helical polypeptides with different side charged groups (amine and guanidine) and hydrophobicity, and mechanistically unraveled the effect of polypeptide structure on the gene delivery capability. Guanidine-containing polypeptides displayed superior membrane activities to their amine-containing analogues via the pore formation mechanism, and thus possessed notably higher transfection efficiencies. Elongating the hydrophobic side chain also potentiated the membrane activities of the polypeptides, while at the meantime caused higher cytotoxicities. Upon an optimal balance between membrane activity and cytotoxicity, maximal transfection efficiency was achieved which outperformed commercial reagent Lipofectamine™ 2000 (LPF2000) by 3-6 folds. This study thus provides mechanistic insights into the rational design of non-viral gene delivery vectors, and the best-performing materials identified also serve as a promising addition to the existing systems.
The rational design of effective and safe non-viral gene vectors is ln class="Chemical">argely dependent onpan> the unpan>derstanding of the structure-property relationship. We hereinpan> report the design of a new series of cationpan>ic, α-helical polypeptides with different side chn class="Chemical">arged groups (amine and guanidine) and hydrophobicity, and mechanistically unraveled the effect of polypeptide structure on the gene delivery capability. Guanidine-containing polypeptides displayed superior membrane activities to their amine-containing analogues via the pore formation mechanism, and thus possessed notably higher transfection efficiencies. Elongating the hydrophobic side chain also potentiated the membrane activities of the polypeptides, while at the meantime caused higher cytotoxicities. Upon an optimal balance between membrane activity and cytotoxicity, maximal transfection efficiency was achieved which outperformed commercial reagent Lipofectn class="Chemical">amine™ 2000 (LPF2000) by 3-6 folds. This study thus provides mechanistic insights into the rational design of non-viral gene delivery vectors, and the best-performing materials identified also serve as a promising addition to the existing systems.
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