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Lipid Nanoparticles Elicit Reactogenicity and Sickness Behavior in Mice Via Toll-Like Receptor 4 and Myeloid Differentiation Protein 88 Axis.

Author information

Affiliations

  • 1. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 S Moody Avenue, Portland, Oregon 97201, United States.
      Authors
    • Korzun T 1, 3
    • Moses AS 1
    • Jozic A 1
    • Grigoriev V 1
    • Kim J 1
    • Le N 1
    • Singh P 1
    • Sharma KS 1
    • Goo YT 1
    • Mamnoon B 1
    • Raitmayr C 1
    • Mesquita Souza AP 1
    • Taratula OR 1
    • Sahay G 1
    • Taratula O 1
    (15 authors)
  • 2. Papé Family Pediatric Research Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code L481, Portland, Oregon 97239, United States.
      Authors
    • Newton S 2
    • Diba P 2, 3
    • Levasseur PR 2
    (3 authors)
  • 3. Medical Scientist Training Program, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.
      Authors
    • Korzun T 1, 3
    • Diba P 2, 3
    (2 authors)
  • 4. Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, 2720 S Moody Avenue, Portland, Oregon 97201, United States.
      Authors
    • Sattler A 4
    (1 author)
  • 5. Endevica Bio, 1935 Techny Rd, Northbrook, Illinois 60062, United States.
      Authors
    • Marks DL 5
    (1 author)

ORCIDs linked to this article

Show all (6)

ACS Nano, 26 Aug 2024, 18(36):24842-24859
https://doi.org/10.1021/acsnano.4c05088 PMID: 39186628 

Abstract 

mRNA therapeutics encapsulated in lipid nanoparticles (LNPs) offer promising avenues for treating various diseases. While mRNA vaccines anticipate immunogenicity, the associated reactogenicity of mRNA-loaded LNPs poses significant challenges, especially in protein replacement therapies requiring multiple administrations, leading to adverse effects and suboptimal therapeutic outcomes. Historically, research has primarily focused on the reactogenicity of mRNA cargo, leaving the role of LNPs understudied in this context. Adjuvanticity and pro-inflammatory characteristics of LNPs, originating at least in part from ionizable lipids, may induce inflammation, activate toll-like receptors (TLRs), and impact mRNA translation. Knowledge gaps remain in understanding LNP-induced TLR activation and its impact on induction of animal sickness behavior. We hypothesized that ionizable lipids in LNPs, structurally resembling lipid A from lipopolysaccharide, could activate TLR4 signaling via MyD88 and TRIF adaptors, thereby propagating LNP-associated reactogenicity. Our comprehensive investigation utilizing gene ablation studies and pharmacological receptor manipulation proves that TLR4 activation by LNPs triggers distinct physiologically meaningful responses in mice. We show that TLR4 and MyD88 are essential for reactogenic signal initiation, pro-inflammatory gene expression, and physiological outcomes like food intake and body weight─robust metrics of sickness behavior in mice. The application of the TLR4 inhibitor TAK-242 effectively reduces the reactogenicity associated with LNPs by mitigating TLR4-driven inflammatory responses. Our findings elucidate the critical role of the TLR4-MyD88 axis in LNP-induced reactogenicity, providing a mechanistic framework for developing safer mRNA therapeutics and offering a strategy to mitigate adverse effects through targeted inhibition of this pathway.

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Read article at publisher's site: https://doi.org/10.1021/acsnano.4c05088

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Funding 

Funders who supported this work.

College of Pharmacy, Oregon State University

    Knight Cancer Institute, Oregon Health and Science University

      National Cancer Institute (2)

      National Center for Advancing Translational Sciences (1)

      Oregon Health and Science University