Non-Modified CpG Oligodeoxynucleotide Forming Guanine-Quadruplex Structure Complexes with ε-Poly-<sub>L</sub>-Lysine Induce Antibody Production as Vaccine Adjuvants
Unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) induce inflammatory cytokines and type I interferons (IFNs) to activate the immune system. To apply CpG ODNs as vaccine adjuvants, the cellular uptake and stability of phosphodiester-based, non-modified ODNs require further i...
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MDPI AG
2022-12-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/12/1868 |
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| author | Dandan Zhao Anh Thi Tram Tu Miwako Shobo Nguyen Bui Thao Le Chiaki Yoshikawa Kazuhisa Sugai Yoji Hakamata Tomohiko Yamazaki |
| author_facet | Dandan Zhao Anh Thi Tram Tu Miwako Shobo Nguyen Bui Thao Le Chiaki Yoshikawa Kazuhisa Sugai Yoji Hakamata Tomohiko Yamazaki |
| author_sort | Dandan Zhao |
| collection | DOAJ |
| description | Unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) induce inflammatory cytokines and type I interferons (IFNs) to activate the immune system. To apply CpG ODNs as vaccine adjuvants, the cellular uptake and stability of phosphodiester-based, non-modified ODNs require further improvement. Previously developed new CpG ODNs forming guanine-quadruplex (G4) structures showed higher nuclease resistance and cellular uptake than linear CpG ODNs; however, the complex formation of G4-CpG ODNs with antigen proteins is necessary for their application as vaccine adjuvants. In this study, we utilized a cationic polymer, ε-poly-<sub>L</sub>-lysine (ε-PLL), as a carrier for G4-CpG ODNs and antigen. The ε-PLL/G4-CpG ODN complex exhibited enhanced stability against nucleases. Cellular uptake of the ε-PLL/G4-CpG ODN complex positively correlated with the N/P ratio. In comparison to naked G4-CpG ODNs, the ε-PLL/G4-CpG ODN complex induced extremely high levels of interleukin (IL)-6, IL-12, and IFN-β. Relative immune cytokine production was successfully tuned by N/P ratio modification. Mice with the ε-PLL/G4-CpG ODN/ovalbumin (OVA) complex showed increased OVA-specific immunoglobulin (Ig)G, IgG1, and IgG2c levels, whereas total IgE levels did not increase and weight gain rates were not affected. Therefore, ε-PLL can serve as a safe and effective phosphodiester-based, non-modified CpG ODN delivery system, and the ε-PLL/G4-CpG ODN/antigen complex is a highly promising candidate for vaccine adjuvants and can be further used in clinical research. |
| first_indexed | 2024-03-09T17:16:14Z |
| format | Article |
| id | doaj.art-6ef1dd2e953845d6a0c35f511174d7f1 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T17:16:14Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-6ef1dd2e953845d6a0c35f511174d7f12023-11-24T13:34:47ZengMDPI AGBiomolecules2218-273X2022-12-011212186810.3390/biom12121868Non-Modified CpG Oligodeoxynucleotide Forming Guanine-Quadruplex Structure Complexes with ε-Poly-<sub>L</sub>-Lysine Induce Antibody Production as Vaccine AdjuvantsDandan Zhao0Anh Thi Tram Tu1Miwako Shobo2Nguyen Bui Thao Le3Chiaki Yoshikawa4Kazuhisa Sugai5Yoji Hakamata6Tomohiko Yamazaki7Research Center for Functional Materials (RCFM), National Institute for Materials Science (NIMS), 1-2-1, Sengen, Tsukuba 305-0047, JapanResearch Center for Functional Materials (RCFM), National Institute for Materials Science (NIMS), 1-2-1, Sengen, Tsukuba 305-0047, JapanResearch Center for Functional Materials (RCFM), National Institute for Materials Science (NIMS), 1-2-1, Sengen, Tsukuba 305-0047, JapanResearch Center for Functional Materials (RCFM), National Institute for Materials Science (NIMS), 1-2-1, Sengen, Tsukuba 305-0047, JapanResearch Center for Functional Materials (RCFM), National Institute for Materials Science (NIMS), 1-2-1, Sengen, Tsukuba 305-0047, JapanSchool of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, 1-7-1 Kyonancho, Musashino-shi, Tokyo 180-8602, JapanSchool of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, 1-7-1 Kyonancho, Musashino-shi, Tokyo 180-8602, JapanResearch Center for Functional Materials (RCFM), National Institute for Materials Science (NIMS), 1-2-1, Sengen, Tsukuba 305-0047, JapanUnmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) induce inflammatory cytokines and type I interferons (IFNs) to activate the immune system. To apply CpG ODNs as vaccine adjuvants, the cellular uptake and stability of phosphodiester-based, non-modified ODNs require further improvement. Previously developed new CpG ODNs forming guanine-quadruplex (G4) structures showed higher nuclease resistance and cellular uptake than linear CpG ODNs; however, the complex formation of G4-CpG ODNs with antigen proteins is necessary for their application as vaccine adjuvants. In this study, we utilized a cationic polymer, ε-poly-<sub>L</sub>-lysine (ε-PLL), as a carrier for G4-CpG ODNs and antigen. The ε-PLL/G4-CpG ODN complex exhibited enhanced stability against nucleases. Cellular uptake of the ε-PLL/G4-CpG ODN complex positively correlated with the N/P ratio. In comparison to naked G4-CpG ODNs, the ε-PLL/G4-CpG ODN complex induced extremely high levels of interleukin (IL)-6, IL-12, and IFN-β. Relative immune cytokine production was successfully tuned by N/P ratio modification. Mice with the ε-PLL/G4-CpG ODN/ovalbumin (OVA) complex showed increased OVA-specific immunoglobulin (Ig)G, IgG1, and IgG2c levels, whereas total IgE levels did not increase and weight gain rates were not affected. Therefore, ε-PLL can serve as a safe and effective phosphodiester-based, non-modified CpG ODN delivery system, and the ε-PLL/G4-CpG ODN/antigen complex is a highly promising candidate for vaccine adjuvants and can be further used in clinical research.https://www.mdpi.com/2218-273X/12/12/1868guanine quadruplexCpG oligodeoxynucleotidesε-poly-<sub>L</sub>-lysineimmune stimulationcytokine induction |
| spellingShingle | Dandan Zhao Anh Thi Tram Tu Miwako Shobo Nguyen Bui Thao Le Chiaki Yoshikawa Kazuhisa Sugai Yoji Hakamata Tomohiko Yamazaki Non-Modified CpG Oligodeoxynucleotide Forming Guanine-Quadruplex Structure Complexes with ε-Poly-<sub>L</sub>-Lysine Induce Antibody Production as Vaccine Adjuvants Biomolecules guanine quadruplex CpG oligodeoxynucleotides ε-poly-<sub>L</sub>-lysine immune stimulation cytokine induction |
| title | Non-Modified CpG Oligodeoxynucleotide Forming Guanine-Quadruplex Structure Complexes with ε-Poly-<sub>L</sub>-Lysine Induce Antibody Production as Vaccine Adjuvants |
| title_full | Non-Modified CpG Oligodeoxynucleotide Forming Guanine-Quadruplex Structure Complexes with ε-Poly-<sub>L</sub>-Lysine Induce Antibody Production as Vaccine Adjuvants |
| title_fullStr | Non-Modified CpG Oligodeoxynucleotide Forming Guanine-Quadruplex Structure Complexes with ε-Poly-<sub>L</sub>-Lysine Induce Antibody Production as Vaccine Adjuvants |
| title_full_unstemmed | Non-Modified CpG Oligodeoxynucleotide Forming Guanine-Quadruplex Structure Complexes with ε-Poly-<sub>L</sub>-Lysine Induce Antibody Production as Vaccine Adjuvants |
| title_short | Non-Modified CpG Oligodeoxynucleotide Forming Guanine-Quadruplex Structure Complexes with ε-Poly-<sub>L</sub>-Lysine Induce Antibody Production as Vaccine Adjuvants |
| title_sort | non modified cpg oligodeoxynucleotide forming guanine quadruplex structure complexes with ε poly sub l sub lysine induce antibody production as vaccine adjuvants |
| topic | guanine quadruplex CpG oligodeoxynucleotides ε-poly-<sub>L</sub>-lysine immune stimulation cytokine induction |
| url | https://www.mdpi.com/2218-273X/12/12/1868 |
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