2. Academic Validation
  3. Splenic B cell-targeting lipid nanoparticles for safe and effective mRNA vaccine delivery

Splenic B cell-targeting lipid nanoparticles for safe and effective mRNA vaccine delivery

  • J Control Release. 2025 Jun 10:382:113687. doi: 10.1016/j.jconrel.2025.113687.
Yuichi Suzuki 1,  Mai Yakuwa 1,  Mina Sato 2,  Eleni Samaridou 3,  Moritz Beck-Broichsitter 3,  Masatoshi Maeki 4,  Manabu Tokeshi 4,  Yuma Yamada 5,  Hideyoshi Harashima 2,  Yusuke Sato 6
Affiliations

Affiliations

  • 1 Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
  • 2 Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Hokkaido University, Institute for Vaccine Research and Development (HU-IVReD).
  • 3 Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
  • 4 Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, Kita-13 Nishi-8, Kita-ku, Sapporo 060-8628, Japan.
  • 5 Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Hokkaido University, Institute for Vaccine Research and Development (HU-IVReD).
  • 6 Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Hokkaido University, Institute for Vaccine Research and Development (HU-IVReD). Electronic address: y_sato@pharm.hokudai.ac.jp.
PMID: 40187650 DOI: 10.1016/j.jconrel.2025.113687
Abstract

mRNA-loaded lipid nanoparticles (LNPs) have emerged as a potent and versatile platform that underpins the success of mRNA vaccines, but guidelines for designing safe and effective formulations with minimal off-target effects remain unclear. In this study, we focused on a rational design for a novel ionizable lipid library that is based on ionizable tri-oleoyl-tris (iTOT) compounds with a high yield via a simple 2-step synthesis. To further enhance the efficacy and safety of this potent library for vaccine applications, we identified the optimal composition for a vaccine by focusing on the molar ratio of specific lipid excipients in the formulation. This composition brought about a shift in delivery to the spleen, and the LNP formulation, which contained 15 mol% DSPC (15%DSPC-LNPs), was thoroughly taken up by both B cells and Other splenic immune cells. This formulation requires neither additional lipid components nor targeting ligand modifications, and it is accompanied by antigen-specific cytotoxic T lymphocyte responses. The rigid, hydrophobic, and charge-neutral surface of 15%DSPC-LNPs minimizes Apolipoprotein E-dependent hepatic uptake and maximizes complement receptor-mediated B-cell targeting. Furthermore, as an intramuscularly administered vaccine, 15%DSPC-LNPs induce antigen-specific immune responses and, importantly, results in significantly lower levels of hepatotoxicity compared with that of the mRNA vaccine formulations currently being marketed. In summary, this study demonstrated how the passive targeting of mRNA-LNPs to organs and cells could be regulated by designing novel ionizable lipids combined with adjusting the relative proportions of lipid components. The results of this study also emphasize how selective mRNA delivery to the spleen could avoid the liver, which highlights a promising strategy for the development of safe and effective vaccines.

Keywords

Extrahepatic targeting; Ionizable lipids; Lipid nanoparticle; Marginal zone B cell; Passive targeting; Protein corona; Vaccine; mRNA.

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