Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE)

"1. Introduction

... Lipid nanoparticles [LNPs] are a versatile class of synthetic nanocarriers, consisting generally of a mixture of phospholipid, sterol, PEGylated lipid, and ionizable lipid that become charged in the low endosomal pH. Compared to conventional cationic liposomes, LNPs are considered as relatively safe carriers for mRNA delivery supported by comprehensive studies. However, the drug carrier properties of LNP still have the risk of inducing side effects, and this topic has received less attention in the literature. Therefore, it is necessary to define their safety and therapeutic efficacy under defined physiological conditions to be able to characterize their therapeutic margin for specific clinical indications more accurately. Previously, we investigated the efficacy of modmRNA-LNP in naive animals. LNP delivery requires mechanisms to enable the nucleic acid cargo to enter the cell and escape from intracellular endosomes, thus potentially eliciting innate immune pathways. While such immune activation could be a desirable advantage for vaccination, in other indications it can be detrimental to treatment success and predispose patients to unexpected adverse reactions. Thus, understanding the impact of modmRNA-LNP on innate immune activation or in the setting of ongoing immune activation in diseased states can be greatly beneficial towards clinical implementation of these therapeutics.

To bridge this gap, here we studied the effects of modmRNA-LNP in healthy mice vs. mice experiencing lipopolysaccharide (LPS) induced inflammatory responses. Although fairly benign in the healthy state, LNP potentiated existing inflammation in mice that had received the bacterial cell wall component LPS intratracheally (IT) or intravenously (IV). This is the first indication of this phenomenon of inflammation-exacerbation (IE) by LNP...

5. Conclusion

We report the discovery of inflammation exacerbation (IE) mediated through acute LPS-induced inflammation and LNP delivery. IE was first characterized with very high levels of pro-inflammatory cytokine concentrations in liver tissue and in serum. We further provide evidence that IE is both inflammatory reagent- and LNP-specific, and the phenomena is independent from mRNA cargo. Additionally, IE is a time-sensitive and dose-dependent event. We also show the effect of IE can be alleviated with corticosteroids, such as Dexamethasone. Altogether, our discovery of LPS and LNP-mediated IE will likely provide new information on the potential behavior of benign modmRNA-LNP in specific conditions and advance understanding on potential adverse effects."