ArticleACS nano2024
Lipid Nanoparticles Elicit Reactogenicity and Sickness Behavior in Mice Via Toll-Like Receptor 4 and Myeloid Differentiation Protein 88 Axis.
Article in ACS nano, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Harnessing plant growth-promoting bacteria for nanoparticle biosynthesis: a systematic review of mechanisms, agricultural applications, and biomedical potential.Bioprocess and biosystems engineering · 2026Pooled it
- Ionizable Lipid-Dependent Optimization of Steroid Lipid Nanoparticles With Tunable Immunomodulatory Properties.Advanced materials (Deerfield Beach, Fla.) · 2026Article
- Lipid nanoparticles as active biointerfaces: From membrane interaction to systemic dysregulation.Acta pharmaceutica Sinica. B · 2026Review
- Critical chemistry manufacturing and controls considerations for mRNA lipid nanoparticle translation.Discover nano · 2026Review
- Single-ligand dual-targeting lipid nanoparticles for therapeutic mRNA delivery to glioblastoma across the blood-brain barrier.Journal of controlled release : official journal of the Controlled Release Society · 2026Article
- Review
- Unlocking the potential of mRNA nanomedicines for comprehensive fibrosis therapy.Molecular therapy. Nucleic acids · 2026Review
- Endogenous targeting lipid nanoparticles for systemic mRNA delivery to lung cancer tumors.Journal of controlled release : official journal of the Controlled Release Society · 2026Article
- Localized NF-κB Inhibition Reduces Lipid Nanoparticle-Associated Inflammation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Decoding Undesirable Inflammatory Responses of Nucleic Acid-Delivering Lipid Nanoparticles.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Gene therapy for liver diseases: methods, challenges and opportunities.Journal of nanobiotechnology · 2026Review
- Mitochondrial vulnerability underlies myocarditis from COVID-19 mRNA vaccine.Nature communications · 2026Article
- Inflammatory mediators of mRNA vaccine-induced adverse reactions in mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Lipid nanoparticle-encapsulated microRNA-192: An anti-inflammatory adjuvant that enhances vaccine efficacy in aged mice.Molecular therapy. Nucleic acids · 2026Article
- FAST-CRISPR: Fusogenic Association and Secured Transfection of CRISPR/Cas9 Ribonucleoproteins Using Lipid-Silica Hybrid Nanoparticles for Therapeutic Genome Editing.Small (Weinheim an der Bergstrasse, Germany) · 2026Article
- Development of a Prophylactic mRNA Vaccine for Severe Fever with Thrombocytopenia Syndrome Using HSA based LNP.NPJ vaccines · 2026Article
- Combining Anti-Inflammatory Drugs and Cell-Specific Expression-Suppression Reduces the Adjuvant Activity of mRNA-LNPs.Molecular pharmaceutics · 2026Article
- COVID vaccination and post-infection cancer signals: Evaluating patterns and potential biological mechanisms.Oncotarget · 2026Review
- Myocarditis After mRNA Vaccination: A Metabolic-Innate Immune Cascade Centered on Lipid Nanoparticles.Mediators of inflammation · 2026Review
- Nanomedicine-Empowered CAR-T Therapy for Multiple Myeloma: Toward Programmable, Durable, and Precision Immunotherapy.International journal of nanomedicine · 2026Review
Corrections and comments
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Authors and funding
20 authors.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.