title: A Targeted and Stable Polymeric Nanoformulation Enhances Systemic Delivery of mRNA to Tumors.
abstract: The high vulnerability of mRNA necessitates the manufacture of delivery vehicles to afford adequate protection in the biological milieu. Here, mRNA was complexed with a mixture of cRGD-poly(ethylene glycol) (PEG)-polylysine (PLys) (thiol) and poly(N-isopropylacrylamide) (PNIPAM)-PLys(thiol). The ionic complex core consisting of opposite-charged PLys and mRNA was crosslinked though redox-responsive disulfide linkage, thereby avoiding structural disassembly for exposure of mRNA to harsh biological environments. Furthermore, PNIPAM contributed to prolonged survival in systemic circulation by presenting a spatial barrier in impeding accessibility of nucleases, e.g., RNase, due to the thermo-responsive hydrophilic-hydrophobic transition behavior upon incubation at physiological temperature enabling translocation of PNIPAM from shell to intermediate barrier. Ultimately, the cRGD ligand attached to the formulation demonstrated improved tumor accumulation and potent gene expression, as manifested by virtue of facilitated cellular uptake and intracellular trafficking. These results indicate promise for the utility of mRNA as a therapeutic tool for disease treatment.
authors.affiliation: CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering, Suzhou 215163, China; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: qixian@mit.edu.
authors.forename: Qixian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
authors.forename: Ruogu
authors.initials: R
authors.lastname: Qi
authors.affiliation: School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, China. Electronic address: xychen@dmu.edu.cn.
authors.forename: Xiyi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Ningbo Institute of Material Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, China.
authors.forename: Sudong
authors.initials: S
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
authors.forename: Haihua
authors.initials: H
authors.lastname: Xiao
authors.affiliation: CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering, Suzhou 215163, China. Electronic address: weifeidong@126.com.
authors.forename: Wenfei
authors.initials: W
authors.lastname: Dong
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004339:Drug Compounding; D016503:Drug Delivery Systems; D006801:Humans; D008024:Ligands; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D011107:Polylysine / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D012333:RNA, Messenger / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D008024:Ligands; D011108:Polymers; D012333:RNA, Messenger; D011107:Polylysine; D011092:Polyethylene Glycols
keywords: gene expression; mRNA delivery; polymeric micelle; thermo-responsive; tumor targeting