Journal article
Redox-responsive, reversibly-crosslinked thiolated cationic helical polypeptides for efficient siRNA encapsulation and delivery
Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, 1304 W Green Street, Urbana, IL 61801, USA.1
Division of Hematology-Oncology, Systems Immunobiology Laboratory, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.2
Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Collaborative Innovation Center of Suzhou, Nano Science and Technology, Soochow University, Suzhou 215123, PR China. Electronic address: lcyin@suda.edu.cn.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.4
Cationic helical polypeptides, although highly efficient for inducing membrane penetration, cannot stably condense siRNA molecules via electrostatic interactions, which greatly limit the gene knockdown efficiency. By developing and crosslinking the thiolated polypeptide via formation of disulfide bonds post formation of the polypeptide/siRNA complexes, we were able to obtain stable complexes without compromising the helical secondary structure as well as the membrane activity of the polypeptide.
As such, the stable polypeptide/siRNA complex was able to notably protect the siRNA cargo from nuclease digestion in the extracellular environment, while the functions of the polypeptide/siRNA complex for effective cellular internalization and endosomal escape are still largely preserved. Because the disulfide is susceptible to cleavage in response to intracellular redox triggers, siRNA release from the complex is expected upon redox triggering by glutathione (GSH) intracellularly and was actually observed upon redox triggers mediated by glutathione (GSH).
With the collective contribution of the potent membrane activity and redox-responsive cargo release profiles, the crosslinked complexes enable efficient gene silencing without appreciable cytotoxicity, thus providing a potential strategy for polypeptide-based intracellular siRNA delivery.
Language: | English |
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Year: | 2015 |
Pages: | 231-239 |
ISSN: | 18734995 and 01683659 |
Types: | Journal article |
DOI: | 10.1016/j.jconrel.2015.02.014 |
ORCIDs: | Zhang, Ruoyan |
Cationic helical polypeptide Cations Cell Survival Complex stability Cross-Linking Reagents Crosslinking Genes, Reporter Glutathione HeLa Cells Humans Luciferases Nucleic Acid Conformation Oxidation-Reduction Peptides Piperidines Polyglutamic Acid Protein Structure, Secondary RNA Interference RNA Stability RNA interference RNA, Small Interfering RNAi Therapeutics Sulfhydryl Compounds Thiolation Transfection poly(gamma-(4-((2-(piperidin-1-yl)ethyl)aminomethyl)benzyl)glutamate) siRNA encapsulation