A DNA Microarray-based Analysis of the Host Response to a Nonviral Gene Carrier: A Strategy for Improving the Immune Response

• Hatakeyama, Hiroto

• Ito, Erika

• Yamamoto, Momoko

• Akita, Hidetaka

• Hayashi, Yasuhiro

• Kajimoto, Kazuaki

• Kaji, Noritada

• Baba, Yoshinobu

• Harashima, Hideyoshi

Abstract

The purpose of this study was to investigate the host response to systemically administered lipid nanoparticles (NPs) encapsulating 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 1581 of the differentially expressed genes could be identified by PEG-unmodified NP using a 3-fold 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 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 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.

Journal

• Molecular Therapy

  Molecular Therapy 19 (8), 1487-1498, 2011-08

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Details

• CRID: 1050845763939509888
• NII Article ID: 120003762627
• ISSN: 15250024
• ISSN: 15250016
• HANDLE: 2115/48250
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles