Journal article
Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE)
Journal of controlled release, v 344, pp 50-61
Apr 2022
PMID: 34953981
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Current nucleoside-modified RNA lipid nanoparticle (modmRNA-LNP) technology has successfully paved the way for the highest clinical efficacy data from next-generation vaccinations against SARS-CoV-2 during the COVID-19 pandemic. However, such modmRNA-LNP technology has not been characterized in common pre-existing inflammatory or immune-challenged conditions, raising the risk of adverse clinical effects when administering modmRNA-LNPs in such cases. Herein, we induce an acute-inflammation model in mice with lipopolysaccharide (LPS) intratracheally (IT), 1 mg kg−1, or intravenously (IV), 2 mg kg−1, and then IV administer modmRNA-LNP, 0.32 mg kg−1, after 4 h, and screen for inflammatory markers, such as pro-inflammatory cytokines. ModmRNA-LNP at this dose caused no significant elevation of cytokine levels in naive mice. In contrast, shortly after LPS immune stimulation, modmRNA-LNP enhanced inflammatory cytokine responses, Interleukin-6 (IL-6) in serum and Macrophage Inflammatory Protein 2 (MIP-2) in liver significantly. Our report identifies this phenomenon as inflammation exacerbation (IE), which was proven to be specific to the LNP, acting independent of mRNA cargo, and was demonstrated to be time- and dose-dependent. Macrophage depletion as well as TLR3 −/− and TLR4−/− knockout mouse studies revealed macrophages were the immune cells involved or responsible for IE. Finally, we show that pretreatment with anti-inflammatory drugs, such as corticosteroids, can partially alleviate IE response in mice. Our findings characterize the importance of LNP-mediated IE phenomena in gram negative bacterial inflammation, however, the generalizability of modmRNA-LNP in other forms of chronic or acute inflammatory and immune contexts needs to be addressed.
[Display omitted]
Metrics
Details
- Title
- Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE)
- Creators
- Hamideh Parhiz - University of PennsylvaniaJacob S. Brenner - Translational TherapeuticsPriyal N. Patel - University of PennsylvaniaTyler E. Papp - University of PennsylvaniaHamna Shahnawaz - University of PennsylvaniaQin Li - University of PennsylvaniaRuiqi Shi - University of PennsylvaniaMarco E. Zamora - Translational TherapeuticsAmir Yadegari - University of PennsylvaniaOscar A. Marcos-Contreras - Translational TherapeuticsAmbika Natesan - University of PennsylvaniaNorbert Pardi - University of PennsylvaniaVladimir V. Shuvaev - Translational TherapeuticsRaisa Kiseleva - Translational TherapeuticsJacob W. Myerson - Translational TherapeuticsThomas Uhler - Translational TherapeuticsRachel S. Riley - University of PennsylvaniaXuexiang Han - University of PennsylvaniaMichael J. Mitchell - University of PennsylvaniaKieu Lam - Genevant Sciences Corporation, Vancouver, BC V5T 4T5, CanadaJames Heyes - Genevant Sciences Corporation, Vancouver, BC V5T 4T5, Canada.Drew Weissman - University of PennsylvaniaVladimir R. Muzykantov - Translational Therapeutics
- Publication Details
- Journal of controlled release, v 344, pp 50-61
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000820188100005
- Other Identifier
- 991020100054904721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
Highly Cited Paper
- Collaboration types
- International collaboration
- Web of Science research areas
- Chemistry, Multidisciplinary
- Pharmacology & Pharmacy