期刊
BIOMATERIALS
卷 34, 期 35, 页码 8979-8990出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2013.08.003
关键词
DNA vaccine; Microarray; Adjuvant; Nanoparticle; Innate immunity
资金
- Next Generation World-Leading Researchers (NEXT program)
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Asahi Glass Foundation
Technologies for the transfection of antigen-encoding genes into the dendritic cells, and subsequent immune-activation are both prerequisites for a successful DNA vaccine. We herein report on the density-dependent enhancement of transgene expression by the simple modification by stearyl-conjugated KALA, an alpha-helical peptide (STR-KALA), onto a lipid envelope-type nanoparticle (the R8-MEND, an octaarginine-modified multifunctional envelope-type nano device). The enhanced transgene expression in the KALA-modified R8-MEND (R8/KALA-MEND) cannot be explained by cellular uptake and nuclear delivery efficacy. Thus, the post-nuclear delivery process (i.e. transcription), but not intracellular trafficking processes attributed the enhanced transfection efficacy. Microarray analyses revealed that transfection with the R8/KALA-MEND resulted in a greater perturbation in host genes expression in comparison with the R8-MEND and that this effect was time-dependent. Further pathway analyses in the category of transcription-related genes and a gene ontology analysis indicated that the R8/KALA-MEND stimulated the expression of transcription factors that are closely related to immune-activation (i.e. NF-kB and STAT). Inhibition of the transfection efficacy by blockage of the STAT pathways revealed that the enhanced transcription activity is the result of immune-stimulation. Collectively, the R8/KALA-MEND mounts a switch-on function that triggers signal transduction forward to the immune-stimulation analogous to an adjuvant, and consequently elicits active transcription. (C) 2013 Elsevier Ltd. All rights reserved.
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