The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
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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In the citing paper
“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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Cites
Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans
Fire, A., Xu, S., Montgomery, M. K., Kostas, S. A., Driver, S. E., & Mello, C. C. (1998) · Nature · doi:10.1038/35888 · Cited by 15,429
Coussens, L. M., & Werb, Z. (2002) · Nature · doi:10.1038/nature01322 · Cited by 15,111
RNA interference is mediated by 21- and 22-nucleotide RNAsPreprint
Elbashir, S. M., Lendeckel, W., & Tuschl, T. (2001) · Genes & Development · doi:10.1101/gad.862301 · Cited by 3,354
Rational design of cationic lipids for siRNA delivery
Semple, S. C., Akinc, A., Chen, J., Sandhu, A. P., Mui, B. L., Cho, C. K., Sah, D. W. Y., Stebbing, D., Crosley, E. J., Yaworski, E., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1602 · Cited by 1,822
RNAi-mediated gene silencing in non-human primates
Zimmermann, T. S., Lee, A. C. H., Akinc, A., Bramlage, B., Bumcrot, D., Fedoruk, M. N., Harborth, J., Heyes, J. A., Jeffs, L. B., John, M., et al. (2006) · Nature · doi:10.1038/nature04688 · Cited by 1,357
Interfering with disease: a progress report on siRNA-based therapeutics
de Fougerolles, A., Vornlocher, H., Maraganore, J. M., & Lieberman, J. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2310 · Cited by 1,223
NanoGenotoxicology: The DNA damaging potential of engineered nanomaterials
Singh, N., Manshian, B. B., Jenkins, G. J. S., Griffiths, S. M., Williams, P. M., Maffeïs, T. G. G., Wright, C. J., & Doak, S. H. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.04.009 · Cited by 1,212
LPS, TLR4 and infectious disease diversity
Miller, S., Ernst, R. K., & Bader, M. W. (2005) · Nature Reviews Microbiology · doi:10.1038/nrmicro1068 · Cited by 1,059
Williams, D. F. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.07.027 · Cited by 971
Lipid-like materials for low-dose, in vivo gene silencing
Love, K. T., Mahon, K. P., Levins, C. G., Whitehead, K. A., Querbes, W., Dorkin, J. R., Qin, J., Cantley, W., Qin, L. L., Racie, T., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910603106 · Cited by 969
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Lipid nanoparticles for mRNA delivery
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Progress and challenges towards targeted delivery of cancer therapeutics
Rosenblum, D., Joshi, N., Tao, W., Karp, J. M., & Peer, D. (2018) · Nature Communications · doi:10.1038/s41467-018-03705-y · Cited by 2,220
Self-citationTreating metastatic cancer with nanotechnology
Schroeder, A., Heller, D. A., Winslow, M. M., Dahlman, J. E., Pratt, G. W., Langer, R., Jacks, T., & Anderson, D. G. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3180 · Cited by 1,175
“Recent studies have identified cytokines that are upregulated after the administration of positively charged nanoparticle”
BackgroundConcepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine
Donahue, N. D., Acar, H., & Wilhelm, S. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.04.008 · Cited by 985
“Mice that were intravenously injected with positively charged lipid nanoparticles experienced severe adverse effects, including hepatotoxicity, weight loss, and a proinflammatory response, compared tomice injectedwith neutral or negatively charged nanoparticles [156].”
BackgroundKnocking down disease: a progress report on siRNA therapeutics
Wittrup, A., & Lieberman, J. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3978 · Cited by 827
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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