title: Maximizing gene delivery efficiencies of cationic helical polypeptides via balanced membrane penetration and cellular targeting.
abstract: The application of non-viral gene delivery vectors is often accompanied with the poor correlation between transfection efficiency and the safety profiles of vectors. Vectors with high transfection efficiencies often suffer from high toxicities, making it unlikely to improve their efficiencies by increasing the DNA dosage. In the current study, we developed a ternary complex system which consisted of a highly membrane-active cationic helical polypeptide (PVBLG-8), a low-toxic, membrane-inactive cationic helical polypeptide (PVBLG-7) capable of mediating mannose receptor targeting, and DNA. The PVBLG-7 moiety notably enhanced the cellular uptake and transfection efficiency of PVBLG-8 in a variety of mannose receptor-expressing cell types (HeLa, COS-7, and Raw 264.7), while it did not compromise the membrane permeability of PVBLG-8 or bring additional cytotoxicities. Because of the simplicity and adjustability of the self-assembly approach, optimal formulations of the ternary complexes with a proper balance between membrane activity and targeting capability were easily identified in each specific cell type. The optimal ternary complexes displayed desired cell tolerability and markedly outperformed the PVBLG-8/DNA binary complexes as well as commercial reagent Lipofectamine™ 2000 in terms of transfection efficiency. This study therefore provides an effective and facile strategy to overcome the efficiency-toxicity poor correlation of non-viral vectors, which contributes insights into the design strategy of effective and safe non-viral gene delivery vectors.
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, 1304 W Green Street, Urbana, IL 61801, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Zheng
authors.forename: Lichen
authors.initials: L
authors.lastname: Yin
authors.forename: Ziyuan
authors.initials: Z
authors.lastname: Song
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Haoyu
authors.initials: H
authors.lastname: Tang
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Gabrielson
authors.forename: Hua
authors.initials: H
authors.lastname: Lu
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000818:Animals; D019556:COS Cells; D002412:Cations / Q000737:chemistry / Q000378:metabolism; D002463:Cell Membrane Permeability; D002522:Chlorocebus aethiops; D004247:DNA / Q000008:administration & dosage*; D006367:HeLa Cells; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014162:Transfection
chemical_list: D002412:Cations; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D010455:Peptides; D011956:Receptors, Cell Surface; D004247:DNA
keywords: Cytotoxicity; Mannose targeting; Membrane penetration; Non-viral gene delivery; Self-assembly; α-Helical polypeptide