title: Multi-Responsive "Turn-On" Nanocarriers for Efficient Site-Specific Gene Delivery In Vitro and In Vivo.
abstract: Systemic gene delivery is a complicated and multistep process that confronts numerous biological barriers. It remains a formidable challenge to exploit a single gene carrier with multiple features to combat all obstacles collectively. Herein, a multi-responsive "turn-on" polyelectrolyte complex (DNA/OEI-SSx/HA-SS-COOH, DSS) delivery system is demonstrated with a sequential self-assembly of disulfide-conjugated oligoethylenimine (OEI-SSx) and disulfide bond-modified hyaluronic acid envelope (HA-SS-COOH) that can combat multiple biological barriers collectively when administered intravenously. DSS is designed to effectively accumulate at the tumor tissue and to be internalized into tumor cells by recognizing CD44. The multi-responsive "turn-on" DSS can respond to the alterations of hyaluronidases and glutathione at both the tumor site and at the intracellular milieu. Sequential degradation and detachment of the HA-SS-COOH envelope followed by the dissociation of the OEI-SSx/DNA inner core contributes to the activation of the endosomal escape and gene release functions, thus greatly enhancing nuclear gene delivery. A systematic investigation of DSS has revealed that the tumor accumulation ability, internalization, and endosome escape of the DSS nanocarriers, DNA unpacking and nuclear transportation are all remarkably improved by the multi-responsive "turn-on" design resulting in highly efficient gene transfection in vitro and in vivo.
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, P. R. China.
authors.forename: Yiyan
authors.initials: Y
authors.lastname: He
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, P. R. China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Ma
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, P. R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Nie
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, P. R. China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yue
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, P. R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Faculty of Science and Engineering, School of Pharmacy, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1SB, UK.
authors.forename: Aisha Roshan Mohamed
authors.initials: AR
authors.lastname: Wali
authors.affiliation: Faculty of Science and Engineering, School of Pharmacy, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1SB, UK.
authors.forename: James Zhenggui
authors.initials: JZ
authors.lastname: Tang
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu, 610064, P. R. China.|College of Materials Science and Engineering, Nanjing Tech University, 30 South Puzhu Road, 211816, Nanjing, P. R. China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry*; D011992:Endosomes / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000737:chemistry; D006821:Hyaluronoglucosaminidase / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D014162:Transfection / Q000379:methods
chemical_list: D004337:Drug Carriers; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D004247:DNA; D006821:Hyaluronoglucosaminidase; D005978:Glutathione
keywords: biological barriers; gene delivery; multi-responsive; nanocarriers; site-specific