Synthetic
oligodeoxynucleotides (ODNs) containing unmethylated
cytosine–phosphate–guanine (CpG) motifs trigger the
immune response by stimulating endosomal Toll-like receptor (TLR)
9. Natural linear ODNs are susceptible to nuclease degradation, thereby
limiting their clinical applications. Here, we designed monomeric
G-quadruplex-based CpG ODNs (G4 CpG ODNs) containing CpG motifs in
the central loop region of the G4 structure. The monomeric G4 CpG
ODNs were more stable in serum than the linear ODNs. The monomeric
G4 CpG ODNs containing two or three CpG motifs induced the production
of immunostimulatory cytokines interleukin (IL)-6, IL-12, and interferon
(IFN)-β in mouse macrophage-like RAW264 cells. We also showed
that the number of CpG motifs and the number of nucleotides between
the CpG motif and G-tracts define the efficacy of the G4 CpG ODNs
in activating TLR9. Incubating human peripheral blood mononuclear
cells with G4 CpG ODNs promoted IL-6 and IFN-γ production, confirming
their stimulatory effects on human immune cells. Mice given intraperitoneal
injections of G4 CpG ODNs produced higher plasma IL-6 compared with
injections of linear ODNs. These findings provide further understanding
of the parameters governing the immunostimulatory activity of G4 CpG
ODNs, thereby providing insights into the rational design of highly
potent G4 CpG ODNs for vaccine adjuvants.
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