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The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation
Abstract
Delivery of nucleic acids with positively charged lipid nanoparticles ((+)NPs) is widely used as research reagents and potentially for therapeutics due to their ability to deliver nucleic acids into the cell cytoplasm. However, in most reports little attention has been made to their toxic effects. In the present study, we performed comprehensive analyses of the potential toxicity associated with (+)NPs. Mice treated with (+)NPs showed increased liver enzyme release and body weight loss compared to mice treated with neutral or negatively charged NPs ((-)NPs), suggesting hepatotoxicity. Intravenous administration of (+)NPs induced interferon type I response and elevated mRNA levels of interferon responsive genes 15-25-fold higher than neutral and (-)NPs in different subsets of leukocytes. Moreover, treatment with (+)NPs provoked a dramatic pro-inflammatory response by inducing Th1 cytokines expression (IL-2, IFN gamma and TNF alpha) 10-75-fold higher than treatment with control particles. Finally, we showed that activation of TLR4 might serve as the underlying mechanism for induction of an immune response when (+)NPs are used. These results suggest that a careful attention must be made when different types of (+)NPs are being developed as nanotherapeutics.
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“Cationic and ionizable lipids have also been reported to stimulate the secretion of pro-inflammatory cytokines and reactive oxygen species170–173.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [170]
In the citing paper
“Although the immunogenicity of these lipids has not yet been fully understood, complement system and Toll-like receptors may participate in innate immune activation170,173–175.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [170]
In the citing paper
“In vivo application of lipid nanoparticles has been reported to induce liver and lung injuries in rodents170,173, which may be attributed to the cytotoxicity of the materials and the induction of”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [170]
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“DOTAP, a cationic lipid-based siRNA-LNP, was found to increase liver enzyme release, suggesting possible hepatoxicity and toll-like receptor-mediated inflammatory response (Kedmi et al., 2010; Landesman-Milo and Peer, 2014).”
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Nucleic acid-based drugs for patients with solid tumours
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Organoids: A new approach in toxicity testing of nanotherapeutics
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Nanoparticle Delivery Systems for DNA/RNA and their Potential Applications in Nanomedicine
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“example of lipid-based nanoparticles, or more generally of engineered nanoparticles, that activate Toll-like receptor 4 [26, 43–46].”
BackgroundCAR Macrophages Engineered In Vivo for Attenuating Myocardial Ischemia-Reperfusion Injury
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High-content analysis for drug delivery and nanoparticle applications
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Nanoparticles for the treatment of osteoporosis
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“Indeed, nanoparticles formulated with DOTAP, the cationic lipid used here, promote a proinflammatory response, with presence of IL-2, IFN-γ , TNF-α , 36 and oligodeoxynucleotides, such as CpG motifs, are able to trigger plasmacytoid dendritic cells, resulting in TNF-α production.”
Reconfigurable Peptide Nanotherapeutics at Tumor Microenvironmental pH
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“55,56 This is particularly relevant in the context of therapeutic applications, where the balance between effective delivery and cellular safety is critical.”
BackgroundAdvanced Strategies in Immune Modulation of Cancer Using Lipid-Based Nanoparticles
Mizrahy, S., Hazan‐Halevy, I., Landesman‐Milo, D., Ng, B. D., & Peer, D. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00069 · Cited by 44
“However, positively charged LNPs have toxic effects including induction of pro-inflammatory response (32).”
BackgroundSelf-citationSmart pH-sensitive nanoassemblies with cleavable PEGylation for tumor targeted drug delivery
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mRNA transfection by a Xentry-protamine cell-penetrating peptide is enhanced by TLR antagonist E6446
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Bioinspired Lipid Nanocarriers for RNA Delivery
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“Unlike cationic lipids, the ionizable lipid has improved tolerability, as cationic lipids have been associated with toxicity and increased immune activation [61].”
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“Of particular interest is that, whereas bulk DOTAP and DOTAP-containing LPNs did not induce any immune activation in the present in vitro studies, DOTAP-containing liposomes did stimulate release of proinflammatory cytokines after in vivo administration in mice.(46) This apparent difference may be attributed to the co…”
ResultClinical translational barriers against nanoparticle-based imaging agents
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Membrane-intercalating conjugated oligoelectrolytes
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“evident that understanding the toxicities of liposomes to immune cells and their effect on the regulation of inflammatory responses are critical factors in avoiding the toxic effects of liposomes and therefore enhancing therapeutic benefits [117].”
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“4 (Bonnet et al., 2008; Gorina et al., 2009; Hollins et al., 2007; Hunter & Moghimi, 2010; Kedmi et al., 2010; Omidi et al., 2005).”
Background
Metadata
- Authors
- Kedmi, R., Ben-Arie, N., & Peer, D.
- Affiliations
- Tel Aviv University (IL)
- Corresponding author
- Peer, Dan
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 31
- Issue
- 26
- Pages
- 6867-6875
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W2126020016
- Cited by
- 546
- References
- 52
- Citations by year
- 2026: 39 · 2025: 60 · 2024: 67 · 2023: 52 · 2022: 54 · 2021: 33 · 2020: 31 · 2019: 29 · 2018: 26 · 2017: 31 · 2016: 14 · 2015: 15 · 2014: 19 · 2013: 27 · 2012: 25
- FWCI
- 9.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- nanoparticle toxicity, TLR4, hepatotoxicity, inflammatory cytokines, Th1 response, nucleic acid delivery, nanotherapeutics, immune activation
- MeSH terms
- Animals, Immunity, Inflammation, Lipids, Mice, Inbred C57BL, Particle Size, Surface Properties, RNA, Small Interfering, Toll-Like Receptor 4, Mice, Nanoparticles
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