Atelocollagen-mediated systemic delivery prevents immunostimulatory adverse effects of siRNA in mammals.
Short interfering RNA (siRNA) is a potent activator of the mammalian innate immune system. When considering possible clinical applications of siRNA for humans, the adverse immunostimulatory effects must also be taken into account. Here, we show that atelocollagen-mediated systemic delivery of siRNA without chemical modifications did not cause any immunostimulation in both animals and human peripheral blood mononuclear cells (PBMCs), even if the siRNA harbored an interferon (IFN)-inducible sequence. In contrast, systemic delivery of immunostimulatory RNA (isRNA)-mediated by a cationic lipid (such as Invivofectamine) induced potent type-I IFNs and inflammatory cytokines. Regarding the mechanism by which the isRNA/atelocollagen complex avoided adverse effects on immunostimulation, we revealed that this complex was not incorporated into PBMCs. On the other hand, Invivofectamine delivered isRNA into PBMCs. The use of either atelocollagen or Invivofectamine as a vehicle elicited significant and undistinguishable therapeutic effects in a contact hypersensitivity (CHS) inflammatory model mouse, when we intravenously injected the siRNA targeting monocyte chemoattractant protein-1 as the complex. For the goal of realizing siRNA-based medicines for humans, atelocollagen is an excellent and promising delivery vehicle, and it has the useful advantage of evading detection by the "radar" of innate immunity.
Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Shinichiro
S
Inaba
Shunji
S
Nagahara
Naoki
N
Makita
Yuzo
Y
Tarumi
Takuji
T
Ishimoto
Seiichi
S
Matsuo
Kenji
K
Kadomatsu
Yoshifumi
Y
Takei
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D003094:Collagen / Q000008:administration & dosage*; D003877:Dermatitis, Contact / Q000276:immunology / Q000628:therapy; D004195:Disease Models, Animal; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000276:immunology; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis; D007677:Kidney Function Tests; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008099:Liver / Q000201:enzymology; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000276:immunology; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D011956:Receptors, Cell Surface / Q000378:metabolism
D000276:Adjuvants, Immunologic; D018932:Chemokine CCL2; D005229:Fatty Acids, Monounsaturated; D018836:Inflammation Mediators; D007370:Interferon Type I; D008562:Membrane Glycoproteins; C474081:Mrc2 protein, mouse; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C059821:atelocollagen; D003094:Collagen; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane