title: Multifunctional oligomer incorporation: a potent strategy to enhance the transfection activity of poly(l-lysine).
abstract: Natural polycations, such as poly(l-lysine) (PLL) and chitosan (CS), have inherent superiority as non-viral vectors due to their unparalleled biocompatibility and biodegradability. However, the application was constrained by poor transfection efficiency and safety concerns. Since previous modification strategies greatly weakened the inherent advantages of natural polycations, developing a strategy for functional group introduction with broad applicability to enhance the transfection efficiency of natural polycations without compromising their cationic properties is imperative. Herein, two uncharged functional diblock oligomers P(DMAEL-b-NIPAM) and P(DMAEL-b-Vlm) were prepared from a lactose derivative, N-iso-propyl acrylamide (NIPAM) as well as 1-vinylimidazole (Vlm) and further functionalized with four small ligands folate, glutathione, cysteine and arginine, respectively, aiming to enhance the interactions of complexes with cells, which were quantified utilizing a quartz crystal microbalance (QCM) biosensor, circumventing the tedious material screening process of cell transfection. Upon incorporation with PLL and DNA, the multifunctional oligomers endow the formulated ternary complexes with great properties suitable for transfection, such as anti-aggregation in serum, destabilized endosome membrane, numerous functional sites for promoted endocytosis and therefore robust transfection activity. Furthermore, different from the conventional strategy of decreasing cytotoxicity by reducing the charge density, the multifunctional oligomer incorporation strategy maintains the highly positive charge density, which is essential for efficient cellular uptake. This system develops a new platform to modify natural polycations towards clinical gene therapy.
authors.affiliation: Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China. tyguo@nankai.edu.cn.
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.affiliation: Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China. tyguo@nankai.edu.cn.
authors.forename: Jixiang
authors.initials: J
authors.lastname: Yang
authors.affiliation: Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China. tyguo@nankai.edu.cn.
authors.forename: Hongqi
authors.initials: H
authors.lastname: Ren
authors.affiliation: Charles Institute of Dermotology, University College Dublin, Dublin 4, Ireland. dezhong.zhou@ucd.ie.
authors.forename: Jonathan
authors.initials: J
authors.lastname: O'Keeffe-Ahern
authors.affiliation: Charles Institute of Dermotology, University College Dublin, Dublin 4, Ireland. dezhong.zhou@ucd.ie.
authors.forename: Dezhong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Science, Nankai University, Tianjin 300071, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Science, Nankai University, Tianjin 300071, China.
authors.forename: Jiatong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China. tyguo@nankai.edu.cn.
authors.forename: Tianying
authors.initials: T
authors.lastname: Guo
mesh_terms: D002412:Cations / Q000737:chemistry*; D048271:Chitosan / Q000737:chemistry* / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004705:Endocytosis / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011107:Polylysine / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism; D014162:Transfection
chemical_list: D002412:Cations; D007093:Imidazoles; D010455:Peptides; D011107:Polylysine; D004247:DNA; D048271:Chitosan; C425704:N-vinylimidazole