A DNA microarray-based analysis of the host response to a nonviral gene carrier: A strategy for improving the immune response

Hiroto Hatakeyama, Erika Ito, Momoko Yamamoto, Hidetaka Akita, Yasuhiro Hayashi, Kazuaki Kajimoto, Noritada Kaji, Yoshinobu Baba, Hideyoshi Harashima

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1487-1498
Number of pages12
JournalMolecular Therapy
Volume19
Issue number8
DOIs
Publication statusPublished - Aug 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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