17,18-epoxyeicosatetraenoic acid ameliorates mRNA-LNP–induced local inflammation by inhibiting neutrophil infiltration

Lipid nanoparticles (LNPs) are a powerful technology for delivering nucleic acids into cells and have greatly contributed to the development of severe acute respiratory syndrome coronavirus 2 mRNA vaccines and nucleic acid-based therapeutics. However, side effects such as pain and swelling at the injection site have been reported after vaccination with severe acute respiratory syndrome coronavirus 2 mRNA, and these are thought to be partly due to LNP-induced inflammation. In this study, we focused on an anti-inflammatory metabolite derived from omega-3 fatty acids and investigated whether it could suppress LNP-induced inflammatory side effects associated with mRNA-LNP vaccination. Intramuscular injection of empty LNPs lacking mRNA elicited inflammatory responses in mice comparable to those induced by mRNA-LNPs. Moreover, neutrophil depletion with an antibody demonstrated that neutrophils are key effector cells in LNP-induced inflammation. To suppress this response, we focused on 17,18-epoxyeicosatetraenoic acid (17,18-EpETE), an omega-3 fatty acid metabolite known to target neutrophils. Intramuscular co-injection of empty LNPs and 17,18-EpETE significantly reduced local swelling and infiltration of immune cells, including neutrophils, at the injection site. Further analysis revealed that this anti-inflammatory effect of 17,18-EpETE was mediated via G protein-coupled receptor 40. Importantly, 17,18-EpETE did not impair antibody production elicited by mRNA-LNP vaccination. These findings suggest that 17,18-EpETE has potential as a supplementary agent to mitigate inflammatory side effects without compromising the immunogenic efficacy of mRNA-LNP vaccines.