Rational design of anti‐inflammatory lipid nanoparticles for mRNA delivery. Issue 5 (25th January 2022)

• Record Type: Journal Article
• Authors: Zhang, Hanwen; Han, Xuexiang; Alameh, Mohamad‐Gabriel; Shepherd, Sarah J.; Padilla, Marshall S.; Xue, Lulu; Butowska, Kamila; Weissman, Drew; Mitchell, Michael J.
• Is Part Of: Journal of biomedical materials research. Volume 110:Issue 5(2022)
• Page Start: 1101
• Page End: 1108
• Publication Date: 2022-01-25
• Subjects: anti‐inflammation -- dexamethasone -- gene delivery -- lipid nanoparticles -- mRNA; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1002/jbm.a.37356
• Languages: English
• ISSNs: 1549-3296

Abstract

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.