2. Academic Validation
  3. Modulating Immunogenicity and Reactogenicity in mRNA-Lipid Nanoparticle Vaccines through Lipid Component Optimization

Modulating Immunogenicity and Reactogenicity in mRNA-Lipid Nanoparticle Vaccines through Lipid Component Optimization

  • ACS Nano. 2025 Aug 5;19(30):27977-28001. doi: 10.1021/acsnano.5c10648.
Yoshino Kawaguchi 1 2,  Mari Kimura 1 3,  Tatsuya Karaki 1 3,  Hiroki Tanaka 4 5,  Chikako Ono 5 6 7,  Tatsuhiro Ishida 2,  Yoshiharu Matsuura 5 6 7,  Toshiro Hirai 1 5 8 9,  Hidetaka Akita 4 5,  Taro Shimizu 1 5 8,  Yasuo Yoshioka 1 3 5 7 8 9 10
Affiliations

Affiliations

  • 1 Vaccine Creation Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 2 Department of Pharmacokinetics and Biopharmaceutics, Graduate School of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, Tokushima 770-8505, Japan.
  • 3 The Research Foundation for Microbial Diseases of Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 4 Laboratory of DDS Design and Drug Disposition, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
  • 5 Center for Advanced Modalities and DDS, The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 6 Laboratory of Virus Control, Research Institute for Microbial Diseases, The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 7 Center for Infectious Disease Education and Research, The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 8 Vaccine Creation Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Institute for Open and Transdisciplinary Research Initiatives, The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 9 Laboratory of Nano-Design for Innovative Drug Development, Graduate School of Pharmaceutical Sciences, The University of Osaka, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 10 Global Center for Medical Engineering and Informatics, The University of Osaka, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
PMID: 40700637 DOI: 10.1021/acsnano.5c10648
Abstract

Messenger RNA (mRNA) vaccines effectively induce antibody production and T cell responses. However, adverse reactions, such as fatigue and fever, following administration remain a key challenge. To modulate the immunogenicity and reactogenicity of mRNA vaccines, the optimization of lipid nanoparticle (LNP) formulations has been attempted, particularly by screening ionizable lipids. In contrast, the potential impact of modifying Other LNP components─poly(ethylene glycol) (PEG)-lipids, Cholesterol, and phospholipids─on overall vaccine effects and adverse reactions remains underexplored. Here, we prepared mRNA-LNP formulations with altered structures and molar ratios of these components to assess their effects on in vivo protein expression, as well as on the induction of antigen-specific immune responses and adverse reactions. Reducing the PEG chain length and molar ratio of PEG-lipids increased antigen-specific antibody and CD8+ T cell responses. LNPs with Cholesterol substituted by plant sterols, or LNPs with Phospholipids replaced by those with different head and tail group structures, induced antigen-specific antibody and CD8+ T cell responses comparable to the control formulation. Alternately, these LNPs significantly reduced inflammatory cytokine production and adverse reactions, including fever, compared with the control LNPs. Finally, correlation analysis revealed a positive association between protein expression in specific organs and the magnitude of immune responses and adverse reactions. These findings demonstrate that modifying PEG-lipids, Cholesterol, and Phospholipids is beneficial for modulating the immunogenicity and reactogenicity of the mRNA-LNP vaccine.

Keywords

PEG-lipids; cholesterol; lipid nanoparticle; mRNA vaccine; phospholipids.

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