Combining Anti-Inflammatory Drugs and Cell-Specific Expression-Suppression Reduces the Adjuvant Activity of mRNA-LNPs

Lipid nanoparticles (LNPs)-encapsulating mRNA (mRNA-LNPs) have become an important modality for vaccine development. mRNA-LNPs also have the ability to introduce therapeutic proteins, which suggests that they should also be a promising modality for gene therapy. However, the intrinsic adjuvant activity of mRNA-LNPs is a fundamental function of the LNPs in RNA vaccines, and this has shown a potential risk of inducing anti-transgene immunity when mRNA-LNPs were used in gene therapy. Therefore, a reduction in the adjuvant activity and adaptive immunity against an expressed protein are prerequisites for therapeutic applications. In this study, two strategies were combined to modulate the adjuvant activity of subcutaneously injected mRNA-LNPs: (1) loading a lipid derivative of dexamethasone to suppress inflammation and (2) inserting a sequence complementary to microRNA-142 into the mRNA to suppress gene expression in immune cells. The combination of these strategies reduced immune reactions against the model antigen ovalbumin in mRNA-LNPs.