TY - JOUR
T1 - A DNA microarray-based analysis of the host response to a nonviral gene carrier
T2 - A strategy for improving the immune response
AU - Hatakeyama, Hiroto
AU - Ito, Erika
AU - Yamamoto, Momoko
AU - Akita, Hidetaka
AU - Hayashi, Yasuhiro
AU - Kajimoto, Kazuaki
AU - Kaji, Noritada
AU - Baba, Yoshinobu
AU - Harashima, Hideyoshi
N1 - Funding Information:
This study was supported by Special Coordination Funds for Promoting Science and Technology of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and Grant for Industrial Technology Research from New Energy and Industrial Technology Development Organization (NEDO), and by Grants-in-Aid for Scientific Research on Priority Areas from the Japan Society for the Promotion of Science (JSPS). We thank M. S. Feather for his helpful advice in writing the English manuscript.
PY - 2011/8
Y1 - 2011/8
N2 - The purpose of this study was to investigate the host response to systemically administered lipid nanoparticles (NPs) encapsulating plasmid DNA (pDNA) in the spleen using a DNA microarray. As a model for NPs, we used a multifunctional envelope-type nano device (MEND). Microarray analysis revealed that 1,581 of the differentially expressed genes could be identified by polyethylene glycol (PEG)-unmodified NP using a threefold change relative to the control. As the result of PEGylation, the NP treatment resulted in the reduction in the expression of most of the genes. However, the expression of type I interferon (IFN) was specifically increased by PEGylation. Based on the microarray and a pathway analysis, we hypothesize that PEGylation inhibited the endosomal escape of NP, and extended the interaction of toll-like receptor-9 (TLR9) with CpG-DNA accompanied by the production of type I IFN. This hypothesis was tested by introducing a pH-sensitive fusogenic peptide, GALA, which enhances the endosomal escape of PEGylated NP. As expected, type I IFN was reduced and interleukin-6 (IL-6) remained at the baseline. These findings indicate that a carrier design based on microarray analysis and the manipulation of intracellular trafficking constitutes a rational strategy for reducing the host immune response to NPs.
AB - The purpose of this study was to investigate the host response to systemically administered lipid nanoparticles (NPs) encapsulating plasmid DNA (pDNA) in the spleen using a DNA microarray. As a model for NPs, we used a multifunctional envelope-type nano device (MEND). Microarray analysis revealed that 1,581 of the differentially expressed genes could be identified by polyethylene glycol (PEG)-unmodified NP using a threefold change relative to the control. As the result of PEGylation, the NP treatment resulted in the reduction in the expression of most of the genes. However, the expression of type I interferon (IFN) was specifically increased by PEGylation. Based on the microarray and a pathway analysis, we hypothesize that PEGylation inhibited the endosomal escape of NP, and extended the interaction of toll-like receptor-9 (TLR9) with CpG-DNA accompanied by the production of type I IFN. This hypothesis was tested by introducing a pH-sensitive fusogenic peptide, GALA, which enhances the endosomal escape of PEGylated NP. As expected, type I IFN was reduced and interleukin-6 (IL-6) remained at the baseline. These findings indicate that a carrier design based on microarray analysis and the manipulation of intracellular trafficking constitutes a rational strategy for reducing the host immune response to NPs.
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U2 - 10.1038/mt.2011.24
DO - 10.1038/mt.2011.24
M3 - Article
C2 - 21386823
AN - SCOPUS:79961031809
SN - 1525-0016
VL - 19
SP - 1487
EP - 1498
JO - Molecular Therapy
JF - Molecular Therapy
IS - 8
ER -