Rational design of anti‐inflammatory lipid nanoparticles for mRNA delivery

Abstract

Lipid nanoparticles (LNPs) play a crucial role in delivering messenger RNA (mRNA) therapeutics for clinical applications, including COVID‐19 mRNA vaccines. While mRNA can be chemically modified to become immune‐silent and increase protein expression, LNPs can still trigger innate immune responses and cause inflammation‐related adverse effects. Inflammation can in turn suppress mRNA translation and reduce the therapeutic effect. Dexamethasone (Dex) is a widely used anti‐inflammatory corticosteroid medication that is structurally similar to cholesterol, a key component of LNPs. Here, we developed LNP formulations with anti‐inflammatory properties by partially substituting cholesterol with Dex as a means to reduce inflammation. We demonstrated that Dex‐incorporated LNPs effectively abrogated the induction of tumor necrosis factor alpha (TNF‐ɑ) in vitro and significantly reduced its expression in vivo. Reduction of inflammation using this strategy improved in vivo mRNA expression in mice by 1.5‐fold. Thus, we envision that our Dex‐incorporated LNPs could potentially be used to broadly to reduce the inflammatory responses of LNPs and enhance protein expression of a range of mRNA therapeutics.

Excipient-Free Ionizable Polyester Nanoparticles for Lung-Selective and Innate Immune Cell Plasmid DNA and mRNA Transfection

“…Examination of the tissue sections did not indicate induction of inflammation nor alterations from normal tissue architecture after polyplex treatment (Figure A). LNP administration has been shown to induce proinflammatory responses, owing to the use of ionizable lipids, and strategies have been developed to reduce this effect. , We analyzed the plasma proinflammatory cytokine levels using an ELISA following polyplex treatment. IL-6 and TNFα and were not significantly increased compared to the PBS control, which demonstrated the lack of proinflammatory responses generated by the polyplexes (Figure B).…”

Quality by Design for enabling RNA platform production processes

“…Finally, in line with the scope expansion of the RNA technology, identifying optimal product characteristics for a given route of administration, therapeutic field, or targeted organ will be crucial. While the optimal immunogenic profile and LNP morphology are both likely to be highly variable, targets for other CQAs could also vary [46]. Among others, while neutral particle surface is desired in current RNA vaccine, surface charge appears to be a crucial parameter in organ targeting and in determining lymph node-and mucus-penetrating ability [47][48][49].…”

Lipid nanoparticles for delivery of RNA therapeutics: Current status and the role of in vivo imaging

“…Additionally, Ndeupen et al reported that robust neutrophil infiltration was found in muscle tissue 24 hours after intramuscular injection of the LNP [178]. This inflammatory response is considered as the causes for the side effect of vaccines and possibly reduce the efficacy to induce the adaptive immunity [179]. Zhang et al reported that an anti-inflammatory (dexamethasone incorporated) luciferase mRNA-loaded LNP showed improved luciferase protein expression compared to conventional LNPs [179].…”

“…This inflammatory response is considered as the causes for the side effect of vaccines and possibly reduce the efficacy to induce the adaptive immunity [179]. Zhang et al reported that an anti-inflammatory (dexamethasone incorporated) luciferase mRNA-loaded LNP showed improved luciferase protein expression compared to conventional LNPs [179]. Therefore, careful assessment of the immune response by LNPs should be conducted during the development of LNP-based platforms [178,180].…”