2. Academic Validation
  3. Rational design of anti-inflammatory lipid nanoparticles for mRNA delivery

Rational design of anti-inflammatory lipid nanoparticles for mRNA delivery

  • J Biomed Mater Res A. 2022 May;110(5):1101-1108. doi: 10.1002/jbm.a.37356.
Hanwen Zhang 1,  Xuexiang Han 1,  Mohamad-Gabriel Alameh 2,  Sarah J Shepherd 1,  Marshall S Padilla 1,  Lulu Xue 1,  Kamila Butowska 1 3,  Drew Weissman 2,  Michael J Mitchell 1 4 5 6 7
Affiliations

Affiliations

  • 1 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 2 Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 3 Intercollegiate Faculty of Biotechnology, University of Gdańsk & Medical Gdańsk, Gdańk, Poland.
  • 4 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 5 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 6 Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 7 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
PMID: 35076171 DOI: 10.1002/jbm.a.37356
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.

Keywords

anti-inflammation; dexamethasone; gene delivery; lipid nanoparticles; mRNA.

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