title: Self-assembling DNA hydrogel-based delivery of immunoinhibitory nucleic acids to immune cells.
abstract: Immunoinhibitory oligodeoxynucleotides (INH-ODNs) are promising inhibitors of Toll-like receptor 9 (TLR9) activation. To efficiently deliver INH-ODNs to TLR9-positive cells, we designed a Takumi-shaped DNA (Takumi) consisting of two partially complementary ODNs as the main component of a DNA hydrogel. Polyacrylamide gel electrophoresis showed that Takumi-containing INH-ODNs (iTakumi) and iTakumi-based DNA hydrogel (iTakumiGel) were successfully generated. Their activity was examined in murine macrophage-like RAW264.7 cells and DC2.4 dendritic cells by measuring tumor necrosis factor-α and interleukin-6 release after the addition of a TLR9 ligand (CpG ODN). Cytokine release was efficiently inhibited by the iTakumiGel. Flow cytometry analysis and confocal microscopy showed that cellular uptake of INH-ODN was greatly increased by the iTakumiGel. These results indicate that a Takumi-based DNA hydrogel is useful for the delivery of INH-ODNs to immune cells to inhibit TLR9-mediated hyperinduction of proinflammatory cytokines. From the Clinical Editor: Toll-like receptor 9 activation has been reported to be associated with many autoimmune diseases. DNA inhibition using oligodeoxynucleotides is one of the potential treatments. In this article, the authors described hydrogel-based platform for the delivery of the inhibitory oligodeoxynucleotides for enhanced efficacy. The positive findings could indicate a way for the future.
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Nishida
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Ohtsuki
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Araie
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Umeki
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Endo
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Emura
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Hidaka
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Sakyo-ku, Kyoto, Japan; Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Takakura
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan. Electronic address: makiya@pharm.kyoto-u.ac.jp.
authors.forename: Makiya
authors.initials: M
authors.lastname: Nishikawa
mesh_terms: D000818:Animals; D002460:Cell Line; D003460:Crystallization / Q000379:methods; D004247:DNA / Q000008:administration & dosage* / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D053769:Nanocapsules / Q000737:chemistry / Q000648:ultrastructure; D051217:Toll-Like Receptor 9 / Q000032:analysis / Q000276:immunology*
chemical_list: D020100:Hydrogels; D007166:Immunosuppressive Agents; D053769:Nanocapsules; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D004247:DNA
keywords: CpG motif; DNA hydrogel; Immunoinhibitory oligodeoxynucleotide; Toll-like receptor 9