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ResearchIn-Press PreviewImmunologyInfectious disease Open Access | 10.1172/JCI204021

Jet-injected combinational adjuvants potentiate naked mRNA vaccines for protection against respiratory viral infections in mice

Nan Qiao,1 Junichi Ishikawa,1 Fumihiko Yasui,2 Kaori Sano,3 Kei Miyakawa,3 Akimasa Hayashi,5 Ahmad Faisal Amiry,6 Haonan Liu,1 Xueyang Zhu,1 Naoko Takeda-Miyata,7 Motohiro Kojima,7 Taku Sato,8 Renata Pasqualini,9 Wadih Arap,10 Kazunori Kataoka,11 Hideki Hasegawa,3 Michinori Kohara,13 and Satoshi Uchida1

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Qiao, N. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Ishikawa, J. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Yasui, F. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Sano, K. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Miyakawa, K. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Hayashi, A. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Amiry, A. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Liu, H. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Zhu, X. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Takeda-Miyata, N. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Kojima, M. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Sato, T. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Pasqualini, R. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Arap, W. in: PubMed | Google Scholar |

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Kataoka, K. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Hasegawa, H. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Kohara, M. in: PubMed | Google Scholar

1Department of Advanced Nanomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

2Research Center for Infectious Diseases Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

3Influenza Research Center, National Institute of Infectious Diseases, Tokyo, Japan

4Influenza Research Center, National Institute of Infectious Diseases, Tokyo, United States of America

5Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan

6Research Center for Infectious Diseases Medical Sciences, The Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

7Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan

8Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan

9Department of Radiation Oncology, Rutgers Cancer Institute, Newark, United States of America

10Division of Hematology/Oncology, Department of Medicine, Rutgers Cancer Institute, Newark, United States of America

11Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

12Influenza Research Center, National Institute of Infectious Diseases, Japan

13Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Find articles by Uchida, S. in: PubMed | Google Scholar

Published October 20, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI204021.
Copyright © 2026, Qiao et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 20, 2026 - Version history
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Abstract

The use of lipid nanoparticles (LNPs) to enhance delivery and immunogenicity of mRNA vaccines raises safety concerns due to strong reactogenicity. Developing naked mRNA vaccines, which can be delivered through liquid jet-injection to the skin, may offer a safer alternative, but their immunogenicity has been limited. To address this challenge, we screened clinically relevant adjuvants to enhance the efficacy of N1-methyl-pseudouridine-modified naked mRNA jet-injection vaccines in mouse models. Although many adjuvants showed little or inhibitory effects on inducing humoral or cellular immunity—despite their known ability to potentiate conventional non-mRNA vaccine platforms—we identified a combination of aluminum phosphate and CpG oligonucleotide that substantially enhanced both humoral and cellular immune responses with increased IgG2a/IgG1 ratio. This adjuvanted naked mRNA vaccine induced IgG2a and cellular immunity at levels comparable to those achieved with LNPs but with lower local and systemic reactogenicity. Mechanistic investigations revealed key roles for type I interferon and interleukin-6 signaling during immunization. Notably, this vaccine formulation in mice virtually eliminated infection by both SARS-CoV-2 and influenza A virus (A/California/7/2009 H1N1) in plaque-forming assays. Collectively, the adjuvanted naked mRNA jet-injection vaccine represents an effective, and safe platform against infectious diseases, with potential for clinic-ready translational applications.

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