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Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE).
Parhiz, Hamideh; Brenner, Jacob S; Patel, Priyal N; Papp, Tyler E; Shahnawaz, Hamna; Li, Qin; Shi, Ruiqi; Zamora, Marco E; Yadegari, Amir; Marcos-Contreras, Oscar A; Natesan, Ambika; Pardi, Norbert; Shuvaev, Vladimir V; Kiseleva, Raisa; Myerson, Jacob W; Uhler, Thomas; Riley, Rachel S; Han, Xuexiang; Mitchell, Michael J; Lam, Kieu; Heyes, James; Weissman, Drew; Muzykantov, Vladimir R.
  • Parhiz H; Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: parhizh@pennmedicine.upenn.edu.
  • Brenner JS; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • Patel PN; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Papp TE; Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Shahnawaz H; Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Li Q; Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Shi R; Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Zamora ME; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • Yadegari A; Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Marcos-Contreras OA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Natesan A; Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Pardi N; Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Shuvaev VV; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Kiseleva R; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Myerson JW; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Uhler T; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Riley RS; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
  • Han X; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
  • Mitchell MJ; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Car
  • Lam K; Genevant Sciences Corporation, Vancouver, BC V5T 4T5, Canada.
  • Heyes J; Genevant Sciences Corporation, Vancouver, BC V5T 4T5, Canada.
  • Weissman D; Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: dreww@pennmedicine.upenn.edu.
  • Muzykantov VR; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: muzykant@pennmedicine.upenn.edu.
J Control Release ; 344: 50-61, 2022 04.
Article in English | MEDLINE | ID: covidwho-1587321
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Nanoparticles / COVID-19 Type of study: Prognostic study Topics: Vaccines Limits: Animals / Humans Language: English Journal: J Control Release Journal subject: Pharmacology Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Nanoparticles / COVID-19 Type of study: Prognostic study Topics: Vaccines Limits: Animals / Humans Language: English Journal: J Control Release Journal subject: Pharmacology Year: 2022 Document Type: Article