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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]
Citations
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
Cited by
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Items 201–300 of 544
Modified mRNA as a therapeutic tool to induce cardiac regeneration in ischemic heart disease
Hadas, Y., Katz, M. G., Bridges, C. R., & Zangi, L. (2016) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1367 · Cited by 37
“Lipid nanoparticles are very efficient and widely used for in vitro transfection, however they have been found to be toxic for cells, which makes them problematic as a vehicle for in vivo transfection.(82) Polymeric nanoparticles are relatively new and promising biomaterials as vehicles for mRNA delivery, and can medi…”
BackgroundMohtar, N., Parumasivam, T., Gazzali, A. M., Tan, C. S., Tan, M., Othman, R., Rahiman, S. S. F., & Wahab, H. A. (2021) · Cancers · doi:10.3390/cancers13143539 · Cited by 39
“Liposomes have also been reported to induce the upregulation of pro-inflammatory cytokines and the increase in liver enzymes upon intravenous administration of positively charged lipid nanoparticles in healthy C57BL/6 mice [36].”
BackgroundWu, F., & Sokolova, I. M. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.149786 · Cited by 38
Lee, S. G., Kim, C. H., Sung, S. W., Lee, E. S., Goh, M. S., Yoon, H. Y., Kang, M. J., Lee, S. K., & Choi, Y. W. (2018) · International Journal of Nanomedicine · doi:10.2147/ijn.s166021 · Cited by 37
“In general, a change of body weight reflects systemic toxicity.(50) As none of the DTX-treated animals showed acute body weight loss during the experiments, it could be concluded that there was no obvious side effect of the DTX-loaded formulations.”
BackgroundHu, H., Liu, D., Zhao, X., Qiao, M., & Chen, D. (2012) · Drug Development and Industrial Pharmacy · doi:10.3109/03639045.2012.702348 · Cited by 37
Nano-mediated strategy for targeting and treatment of non-small cell lung cancer (NSCLC)
Ashique, S., Garg, A., Mishra, N., Raina, N., Ming, L. C., Tuli, H. S., Behl, T., Rani, R., & Gupta, M. (2023) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-023-02522-5 · Cited by 36
“IV drug delivery of liposome, having positively charged surface, has also been shown to elevate liver enzymes and pro-inflammatory cytokines in healthy C57BL/6 mice with efficient therapeutic activity (Kedmi et al. 2010).”
BackgroundRamadan, E., Ismeal, A. A. A., & Naguib, Y. W. (2024) · Journal of Personalized Medicine · doi:10.3390/jpm14111092 · Cited by 42
Ge, K., Bai, Z., Wang, J., Li, Z., Gao, F., Liu, S., Zhang, L., Gao, F., & Xie, C. (2025) · Advanced Materials · doi:10.1002/adma.202418872 · Cited by 36
Martins, S. M., Wendling, T., Gonçalves, V. M. F., Sarmento, B. F. C. C., & Ferreira, D. (2011) · Journal of Chromatography B · doi:10.1016/j.jchromb.2011.11.023 · Cited by 36
Kubota, K., Kohei, O., Sawaki, K., Li, T., Mitsuoka, K., Sato, T., & Takeoka, S. (2017) · International Journal of Nanomedicine · doi:10.2147/ijn.s136426 · Cited by 36
“On the other hand, Kedmi et al reported cytokine release, including both TNF-α and IL-1β by positively charged lipid nanoparticles via stimulation of TLR4 in addition to immune stimulation by nucleic acids, and TLR4 is known to localize on the cell surface.(54) In this study, because the released amount of TNF-α was h…”
Ben-David-Naim, M., Grad, E., Aizik, G., Nordling‐David, M. M., Moshel, O., Granot, Z., & Golomb, G. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.08.036 · Cited by 37
Pratsinis, A., Fan, Y., Portmann, M., Hammel, M., Kou, P., Sarode, A., Ringler, P., Kováčik, Ľ., Lauer, M. E., Lamerz, J., et al. (2023) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2023.122874 · Cited by 35
Grand Challenges in Modulating The Immune Response with RNAi Nanomedicines
Goldsmith, M., Mizrahy, S., & Peer, D. (2011) · Nanomedicine · doi:10.2217/nnm.11.162 · Cited by 35
Self-citationIbricevic, A., Guntsen, S. P., Zhang, K., Shrestha, R., Liu, Y., Sun, J., Welch, M. J., Wooley, K. L., & Brody, S. L. (2013) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2013.02.006 · Cited by 35
Exosomes as an Emerging Plasmid Delivery Vehicle for Gene Therapy
Wallen, M., Aqil, F., Spencer, W. A., & Gupta, R. C. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15071832 · Cited by 40
“The specific formulation of liposomes has to be carefully controlled because certain cationic lipids used for the delivery of nucleic acids cause hepatotoxicity and inflammation [94].”
BackgroundRNA nanomedicines: the next generation drugs?
Singh, M. S., & Peer, D. (2016) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2015.12.011 · Cited by 34
“In vivo, cationic-NCs can induce immune response (either by interacting with Toll-like receptor (TLR4) or by interacting with other charge recognizing intracellular proteins [18 ,19]) and are marked and eliminated by mononuclear phagocytic system (MPS).”
Self-citationEmerging strategies for nanomedicine in autoimmunity
Thatte, A. S., Billingsley, M. M., Weissman, D., Melamed, J. R., & Mitchell, M. J. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115194 · Cited by 36
“Numerous studies associate this toxicity with the adsorption of serum proteins and the activation of toll-like receptor 4 (TLR4), leading to an increased production of inflammatory cytokines [48 – 50].”
BackgroundQi, W., Ding, D., Zhu, H.-Z., Lu, D., Wang, Y., Ding, J., Yan, W., Jia, M., & Guo, Y. (2013) · Gene Therapy · doi:10.1038/gt.2013.49 · Cited by 32
Engineering lymphocytes with RNAi
Ramishetti, S., & Peer, D. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.12.002 · Cited by 33
Self-citationLoughney, J. W., Minsker, K., Ha, S., & Rustandi, R. R. (2019) · Electrophoresis · doi:10.1002/elps.201900063 · Cited by 38
Current state of, prospects for, and obstacles to mRNA vaccine development
Aljabali, A. A. A., Bashatwah, R. M., Obeid, M. A., Mishra, V., Mishra, Y., Serrano‐Aroca, Á., Lundstrom, K. H., & Tambuwala, M. M. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.103458 · Cited by 35
Lee, D., Shen, A. M., Garbuzenko, O. B., & Minko, T. (2024) · The AAPS Journal · doi:10.1208/s12248-024-00967-x · Cited by 35
“The presence of DOTAP facilitates the encapsulation of negatively charged siRNA through electrostatic interactions and promotes cytoplasmic delivery (51, 52).”
Cell Membrane‐Coated Lipid Nanoparticles for Drug Delivery
Zewail, M. B., Yang, G., Fan, Y., Hui, Y., Zhao, C., & Liu, Y. (2025) · Aggregate · doi:10.1002/agt2.70054 · Cited by 34
Advances in RNAi therapeutic delivery to leukocytes using lipid nanoparticles
Ramishetti, S., Landesman‐Milo, D., & Peer, D. (2016) · Journal of drug targeting · doi:10.3109/1061186x.2016.1172587 · Cited by 32
Self-citationmRNA COVID-19 Vaccines—Facts and Hypotheses on Fragmentation and Encapsulation
Jacques Demongeot, A., & Fougère, C. (2022) · Vaccines · doi:10.3390/vaccines11010040 · Cited by 36
Cellular Uptake Mechanisms of Novel Anionic siRNA Lipoplexes
Kapoor, M., & Burgess, D. J. (2012) · Pharmaceutical Research · doi:10.1007/s11095-012-0952-9 · Cited by 32
“Cationic lipid formulations facilitate efficient siRNA delivery but may cause severe cytotoxicity and/or serum inactivation probably due to their cationic charge (6).”
BackgroundKong, K., Li, B., Chang, Y., Zhao, C., Qiao, H., Jin, M., Wu, X., Fan, W., Wang, L., Qi, Y., et al. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03103-9 · Cited by 31
Sharma, B., Peetla, C., Adjei, I. M., & Labhasetwar, V. D. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.03.011 · Cited by 31
“This can contribute to non-specific effects on tumor growth inhibition as is observed with many cationic lipid-based nanoparticle formations [30, 31].”
BackgroundNishimura, T., Yamada, A., Umezaki, K., Sawada, S., Mukai, S., Sasaki, Y., & Akiyoshi, K. (2017) · Biomacromolecules · doi:10.1021/acs.biomac.7b00937 · Cited by 31
Nanoparticle-plasma Membrane Interactions: Thermodynamics, Toxicity and Cellular Response
Rodríguez‐Hernández, A. G., Vázquez-Duhalt, R., & Saquero, A. H. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666181112090648 · Cited by 32
siRNA-Conjugated Nanoparticles to Treat Ovarian Cancer
Halbur, C. R., Choudhury, N., Chen, M. Y., Kim, J. H., & Chung, E. J. (2019) · SLAS TECHNOLOGY · doi:10.1177/2472630318816668 · Cited by 31
Targeting Neutrophilic Inflammation Using Polymersome-Mediated Cellular Delivery
Robertson, J. D., Ward, J. R., Avila-Olias, M., Battaglia, G., & Renshaw, S. A. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601901 · Cited by 30
“such as TLR4, with consequent activation of leukocytes (61).”
BackgroundA review on tumor-targeting liposomes: Fabrication, mechanism and applications
Basak, S., Das, T. K., & Ganguly, S. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117460 · Cited by 32
Leleux, J. A., Atalis, A., & Roy, K. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.09.063 · Cited by 30
Engineering Nanomaterials to Address Cell-Mediated Inflammation in Atherosclerosis
Allen, S. D., Liu, Y., & Scott, E. A. (2016) · Regenerative Engineering and Translational Medicine · doi:10.1007/s40883-016-0012-9 · Cited by 32
“This benefit is to be weighed against the apparent cytotoxicity of cationic nanomaterials, polymers, and lipids [82].”
BackgroundDistasio, N., Salmon, H., Dierick, F., Ebrahimian, T., Tabrizian, M., & Lehoux, S. (2020) · Advanced Therapeutics · doi:10.1002/adtp.202000196 · Cited by 30
Zhen, Y., Ewert, K. K., Fisher, W. S., Steffes, V. M., Li, Y., & Safinya, C. R. (2021) · Scientific Reports · doi:10.1038/s41598-021-86484-9 · Cited by 30
Anti-viral RNAi nanoparticles protect shrimp against white spot disease
Ufaz, S., Balter, A., Tzror-Azankot, C., Einbender, S., Koshet, O., Shainsky‐Roitman, J., Yaari, Z. A., & Schroeder, A. (2017) · Molecular Systems Design & Engineering · doi:10.1039/c7me00092h · Cited by 30
Harnessing RNAi nanomedicine for precision therapy
Peer, D. (2014) · Molecular and Cellular Therapies · doi:10.1186/2052-8426-2-5 · Cited by 29
“In this manner, it is important to note that there are evidences for toxicities of cationic lipids and polymers ([32] and reviewed in [33-35]).”
Self-citationImmune responses of therapeutic lipid nanoparticles
Chen, W. C., May, J. P., & Li, S. (2012) · Nanotechnology Reviews · doi:10.1515/ntrev-2012-0040 · Cited by 29
Li, Y., Li, M., Gong, T., Zhang, Z., & Sun, X. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.07.034 · Cited by 29
mRNA-based therapeutic strategies for cancer treatment
Taibi, T., Cheon, S., Perna, F., & Vu, L. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.04.035 · Cited by 31
The Interplay of Endosomal Escape and RNA Release from Polymeric Nanoparticles
Cheung, T. H., & Shoichet, M. S. (2025) · Langmuir · doi:10.1021/acs.langmuir.4c05176 · Cited by 33
Zhu, X., Li, R., Xu, L., Yin, H. Y., Chen, L., Yuan, Y., Zhong, W., & Lin, J. (2018) · Small · doi:10.1002/smll.201803428 · Cited by 28
Zhou, D., Liu, S., Hu, Y. J., Yang, S., Zhao, B., Zheng, K., Zhang, Y., He, P., Mo, G., & Li, Y. (2020) · Journal of Materials Chemistry B · doi:10.1039/d0tb00143k · Cited by 28
In vivo peptide-based delivery of a gene-modifying enzyme into cells of the central nervous system
Allen, J. K., Sutherland, T. C., Prater, A. R., Geoffroy, C. G., & Pellois, J. (2022) · Science Advances · doi:10.1126/sciadv.abo2954 · Cited by 30
“However, these approaches require the modification of proteins with fusion tags that can potentially interfere with protein function and the use of lipid-based transfection agents, which may persist inside cells for long periods of time and elicit a variety of cellular responses (46, 47).”
BackgroundPoly (beta‐amino ester) as an in vivo nanocarrier for therapeutic nucleic acids
Nezhad, M. S. (2022) · Biotechnology and Bioengineering · doi:10.1002/bit.28269 · Cited by 28
Advances in Nonviral mRNA Delivery Materials and Their Application as Vaccines for Melanoma Therapy
Neill, B., Romero, A. R., & Fenton, O. S. (2023) · ACS Applied Bio Materials · doi:10.1021/acsabm.3c00721 · Cited by 31
Rastegari, A., Mottaghitalab, F., Dinarvand, R., Amini, M., Arefian, E., Gholami, M., & Atyabi, F. (2019) · Drug Delivery and Translational Research · doi:10.1007/s13346-019-00618-1 · Cited by 28
Design principles of lipid nanoparticles for RNA delivery
Arral, M. L., & Whitehead, K. A. (2026) · Nature Reviews Bioengineering · doi:10.1038/s44222-026-00401-1 · Cited by 41
“In addition, compared to saturated alternatives, such as DSPC 43,179 , DOPE adopts an inverted hexagonal structure in the acidic endosomal environment 180 , and its unsaturated tails create a more fluid lipid layer 33,169 , promoting membrane fusion and disruption 181,182 .”
Dvash, R., Khatchatouriants, A., Solmesky, L. J., Wibroe, P. P., Weil, M., Moghimi, S. M., & Peer, D. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.05.042 · Cited by 27
“24 h post the last injection, blood was drawn and the serum was obtained by centrifugation of the whole blood at 850 g for 15 min in a protocol we previously reported [22] and was applied into a COBAS MIRA auto analyzer (Roche) to analyze the levels of liver enzymes Alanine Aminotransferase (ALT) and Aspartate Aminotr…”
MethodSelf-citationMa, X., Sun, J., Zhong, L., Wang, Y., Huang, Q., Liu, X., Jin, S., Zhang, J., & Liang, X. (2019) · Nano Letters · doi:10.1021/acs.nanolett.9b02826 · Cited by 27
Physicochemical characterization of anionic lipid-based ternary siRNA complexes
Kapoor, M., & Burgess, D. J. (2012) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2012.03.013 · Cited by 28
Tuning the Immunostimulation Properties of Cationic Lipid Nanocarriers for Nucleic Acid Delivery
Dey, A. K., Nougarède, A., Clément, F., Fournier, C., Jouvin‐Marche, E., Escudé, M., Jary, D., Navarro, F. P., & Marche, P. N. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.722411 · Cited by 29
“A previous study has reported that positively charged nanocarriers induce some systemic toxicity and proinflammatory effects (14).”
BackgroundShi, Y., Liu, Y., Huang, J., Luo, Z., Guo, X., Jiang, M., Li, X., Lu, Y., Liu, X., Shan, X., et al. (2022) · Theranostics · doi:10.7150/thno.71760 · Cited by 26
“It should be noted that the cationic lipid DOTAP in CNEs might partially account for the induction of these immunostimulatory molecules (adjuvant effect), and the complement system and toll-like receptors may participate in such immune activation [51, 52].”
BackgroundThe Novelty of mRNA Viral Vaccines and Potential Harms: A Scoping Review
Halma, M. T. J., Rose, J., Jenks, A., & Lawrie, T. A. (2023) · J — Multidisciplinary Scientific Journal · doi:10.3390/j6020017 · Cited by 25
“While the lipid nanoparticle exhibits an acute inflammatory response by itself [77,78,181], the trials using LNPs, so far, have not found a large safety signal when using LNPs to deliver small molecules, non-expressing RNAs, or RNAs for endogenous proteins [77,78,181].”
BackgroundStigliano, C., Aryal, S., Tullio, M. D. D., Nicchia, G. P., Pascazio, G., Svelto, M., & Decuzzi, P. (2013) · Molecular Pharmaceutics · doi:10.1021/mp400224u · Cited by 26
Current Update on the Role of Enhanced Permeability and Retention Effect in Cancer Nanomedicine
Jasim, A. A., Abdelghany, S., & Greish, K. F. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809717-5.00002-6 · Cited by 26
The in vivo toxicological profile of cationic solid lipid nanoparticles
Mendonça, M. C. P., Radaic, A., Garcia-Fóssa, F., da Cruz‐Höfling, M. A., Vinolo, M. A. R., & de Jesus, M. B. (2019) · Drug Delivery and Translational Research · doi:10.1007/s13346-019-00657-8 · Cited by 26
Li, Y., Cui, X., Chen, Q., Yu, J., Zhang, H., Gao, J., Sun, D., & Zhang, G. (2018) · BMC Pharmacology and Toxicology · doi:10.1186/s40360-018-0230-5 · Cited by 26
Yang, Z., Lou, C., Wang, X., Wang, C., Shi, Z., & Niu, N. (2022) · BMC Infectious Diseases · doi:10.1186/s12879-022-07791-8 · Cited by 25
“This phenomenon could be ascribed to the toxicity imparted by the positive surface charge of nanoliposomes [45].”
BackgroundNanoparticles and modulation of immune responses
Pantic, I. V. (2011) · Science Progress · doi:10.3184/003685011x12979697342151 · Cited by 25
Nordling‐David, M. M., & Golomb, G. (2013) · Israel Journal of Chemistry · doi:10.1002/ijch.201300055 · Cited by 26
Peer, D. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.06.029 · Cited by 25
Self-citationLipid nanoparticles technology in vaccines: Shaping the future of prophylactic medicine
Abdellatif, A. A. H., Younis, M. A., Alsowinea, A. F., Abdallah, E. M., Abdel‐Bakky, M. S., Al-Subaiyel, A., Hassan, Y. A., & Tawfeek, H. M. (2022) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2022.113111 · Cited by 24
Emergence of mRNA vaccines in the management of cancer
Razif, M. I. M., Nizar, N., Abidin, N. H. Z., Ali, S. N. M., Zarimi, W. N. N. W., Khotib, J., Darnis, D. S., Jailani, M. T. M., & Taher, M. (2023) · Expert Review of Vaccines · doi:10.1080/14760584.2023.2232450 · Cited by 23
“They are associated with noxious and harmful effects due to their strong positive charge and low endosomal escape in comparison with anionic or neutral lipids [22].”
BackgroundSolmesky, L. J., Shuman, M., Goldsmith, M., Weil, M., & Peer, D. (2011) · Nanotechnology · doi:10.1088/0957-4484/22/49/494016 · Cited by 24
Self-citationLeishmaniasis: focus on the design of nanoparticulate vaccine delivery systems
Doroud, D., & Rafati, S. (2011) · Expert Review of Vaccines · doi:10.1586/erv.11.166 · Cited by 24
Monteiro, L. M., Löbenberg, R., Fotaki, N., de Araújo, G. L. B., Cotrim, P. C., & Bou‐Chacra, N. A. (2019) · Journal of Global Antimicrobial Resistance · doi:10.1016/j.jgar.2019.06.006 · Cited by 24
Harnessing mRNA-lipid nanoparticles as innovative therapies for autoimmune diseases
Razavi, R., Kegel, M., Muscat-Rivera, J., Weissman, D., & Melamed, J. R. (2025) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2025.101566 · Cited by 28
“46 However, permanently cationic lipids were associated with cytotoxicity and systemic inflammation, 47–51 leading to the development of ionizable lipids.”
Liang, H., Zhang, F., Hong, Y., Wu, Y., Xie, H., Zhang, C., Wang, Z., Lu, Z., & Yang, H. (2022) · Small · doi:10.1002/smll.202106046 · Cited by 23
Deng, J., Fukushima, Y., Nozaki, K., Nakanishi, H., Yada, E., Terai, Y., Fueki, K., & Itaka, K. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14091785 · Cited by 27
“Lipid nanoparticles (LNP) are the most commonly used mRNA delivery methods, but the immune–stimulation property of the LNP may interfere with the therapeutic effect of the mRNA, especially for anti-inflammatory therapy [22,23].”
BackgroundMechanisms of solid lipid nanoparticles-triggered signaling pathways in eukaryotic cells
Moraes-Lacerda, T., & de Jesus, M. B. (2022) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2022.112863 · Cited by 23
Shi, W. M., Guan, X., Han, Y., Zha, S., Fang, J., Xiao, G., Yan, M., & Liu, G. (2018) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2018.07.009 · Cited by 23
Nucleic acid targeting: towards personalized therapy for head and neck cancer
Parsel, S. M., Grandis, J. R., & Thomas, S. M. (2015) · Oncogene · doi:10.1038/onc.2015.424 · Cited by 22
Bates, S. M., Munson, M. J., Trovisco, V., Pereira, S. G. T., Miller, S. R., Sabirsh, A., Betts, C. J., Blenke, E. O., & Gay, N. J. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.114047 · Cited by 26
Recent Advances in Lipid Nanoparticles: Nucleic Acid Therapeutics and Targeting Strategies
Sarmah, S., Baidya, S., & De, M. (2025) · Small · doi:10.1002/smll.202506812 · Cited by 25
Du, X., Yada, E., Terai, Y., Takahashi, T., Nakanishi, H., Tanaka, H., Akita, H., & Itaka, K. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15092291 · Cited by 21
“…markers associated with liver and kidney injury [38,39], since previous studies have reported an increase in liver enzymes such as the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the blood following administration of LNP loaded with mRNA, or empty LNP in rodents [10,11].”
BackgroundResultInfluentialQin, Y., Rouatbi, N., Wang, J. T.-W., Baker, R. S., Spicer, J. F., Walters, A. A., & Al‐Jamal, K. T. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.03.018 · Cited by 22
“Some studies have reported that cationic and ionisable lipids could stimulate the secretion of pro-inflammatory cytokines and reactive oxygen species [66 – 68].”
Nanomaterials in the Context of Type 2 Immune Responses—Fears and Potentials
Himly, M., Mills-Goodlet, R., Geppert, M., & Duschl, A. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00471 · Cited by 23
Carrier-free nanodrug-based virus-surface-mimicking nanosystems for efficient drug/gene co-delivery
Sun, X., Li, M., Yang, Y., Jia, H., & Liu, W. (2018) · Biomaterials Science · doi:10.1039/c8bm01033a · Cited by 21
Targeting central nervous system pathologies with nanomedicines
Mizrahy, S., Gutkin, A., Decuzzi, P., & Peer, D. (2018) · Journal of drug targeting · doi:10.1080/1061186x.2018.1533556 · Cited by 22
“However, positively charged NPs have toxic effects including induction of pro-inflammatory response [56].”
BackgroundSelf-citationIdres, Y. M., Idris, A., & Gao, W. (2025) · Drug Delivery and Translational Research · doi:10.1007/s13346-025-01815-x · Cited by 21
“A known risk with LNP delivery platforms includes cytotoxicity and an unfavourable immune response, which can be caused by a highly positive surface charge or stimulation of the innate immune response [44, 45].”
The impact of chemical reactivity on the quality and stability of RNA–LNP pharmaceuticals
Kovačič, T., Haas, H., Stotsky‐Oterin, L., Štrancar, A., Bren, U., & Peer, D. (2025) · Nature Reviews Chemistry · doi:10.1038/s41570-025-00763-x · Cited by 23
“It was later found that cationic lipids may still exhibit high toxicity in vivo 7 .”
Self-citationBiocompatible cationic lipids for the formulation of liposomal DNA vectors
Montis, C., Sostegni, S., Milani, S., Baglioni, P., & Berti, D. (2014) · Soft Matter · doi:10.1039/c4sm00142g · Cited by 20
Emerging Strategies for Immunotherapy of Solid Tumors Using Lipid‐Based Nanoparticles
Fernandes, S., Cassani, M., Cavalieri, F., Forte, G., & Caruso, F. (2023) · Advanced Science · doi:10.1002/advs.202305769 · Cited by 20
Targeting lymph nodes for enhanced cancer vaccination: From nanotechnology to tissue engineering
Wang, J., Zhang, Z., Liang, R., Chen, W., Li, Q., Xu, J., Zhao, H., & Xing, D. (2024) · Materials Today Bio · doi:10.1016/j.mtbio.2024.101068 · Cited by 20
“They also induced a significant pro-inflammatory response by elevating the expression of Th1 cytokines 10 – 75-fold higher compared with control NPs [84].”
BackgroundChitosan and its derivatives as nanocarriers for siRNA delivery
Al‐Qadi, S., Grenha, A., & Remuñán‐López, C. (2012) · Journal of Drug Delivery Science and Technology · doi:10.1016/s1773-2247(12)50003-1 · Cited by 20
Maffioli, C., Grandgirard, D., Leib, S. L., & Engler, O. B. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044703 · Cited by 20
“However they are known to cause side effects such as cytotoxicity and nonspecific activation of intracellular signalling pathways [55,56].”
BackgroundHatakeyama, H., Ito, E., Yamamoto, M., Akita, H., Hayashi, Y., Kajimoto, K., Kaji, N., Baba, Y., & Harashima, H. (2011) · Molecular Therapy · doi:10.1038/mt.2011.24 · Cited by 20
“14 recently reported that the immune activation of DOTAP based cationic lipid nanoparticles containing siRNA might occur via TLR4, which provides support for our prediction [36].”
ResultCamera, G. D., Lipsa, D., Méhn, D., Italiani, P., Boraschi, D., & Gioria, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020820 · Cited by 21
“, already loaded with the drug cargo under investigation) [19,20] and upon intravenous administration.”
BackgroundStructure–activity relationships of pH-responsive and ionizable lipids for gene delivery
Zou, Y., Zhou, Q., Zhao, Y., Zhi, D., Chen, H., Wang, R., Ju, B., & Zhang, S. (2022) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2022.121596 · Cited by 19
Mostafa, N. Z., Talwar, R. M., Shahin, M., Unsworth, L. D., Major, P. W., & Doschak, M. R. (2014) · Tissue Engineering Part A · doi:10.1089/ten.tea.2014.0075 · Cited by 19
“18 30–32 Bone healing consists of well-coordinated series of events, including inflammation, cellular migration, endo-chondral and/or intramembranous bone formation, and re-modeling.”
Can gene editing and silencing technologies play a role in the treatment of head and neck cancer?
Shaikh, M. H., Clarke, D. T. W., Johnson, N. W., & McMillan, N. A. J. (2017) · Oral Oncology · doi:10.1016/j.oraloncology.2017.02.016 · Cited by 19
“Further, NPs can be coated with hydrophilic polymers, such as polyethylene glycol (PEG), to prevent opsonisation by the mononuclear phagocytic system (MPS) and increase circulation time [47,48].”
BackgroundEffect of phosphatidylcholine on the stability and lipolysis of nanoemulsion drug delivery systems
Zhang, B., Zhou, X. M., Miao, Y., Wang, X., Yang, Y., Zhang, X., & Gan, Y. (2020) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2020.119354 · Cited by 18
Thanki, K., Papai, S., Lokras, A. G., Rose, F., Falkenberg, E., Franzyk, H., & Foged, C. (2019) · Pharmaceutical Research · doi:10.1007/s11095-018-2566-3 · Cited by 19
Jbara-Agbaria, D., Blondzik, S., Burger‐Kentischer, A., Agbaria, M., Nordling‐David, M. M., Giterman, A., Aizik, G., Rupp, S., & Golomb, G. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14030633 · Cited by 18
“In addition, the cellular uptake of negatively-charged vesicles is reduced due to electrostatic repulsion of the cell’s membrane, and positively-charged vesicles are associated with relatively low cellular uptake and hemostasis side-effects [72,73].”
BackgroundLi, Y., Yao, R., Ren, M., Yuan, K., Du, Y., He, Y., Kang, H., Yuan, S., Ju, W., Qiao, J., et al. (2022) · Journal of Lipid Research · doi:10.1016/j.jlr.2022.100273 · Cited by 18
“focused on the toxic of drug carriers on macrophages in the MPS in vivo (66, 67).”
BackgroundNew insights into nanosystems for non-small-cell lung cancer: diagnosis and treatment
Jiang, P., Liang, B., Zhang, Z., Fan, B., Zeng, L., Zhou, Z., Mao, Z., Xu, Q., Yao, W., & Shen, Q. (2023) · RSC Advances · doi:10.1039/d3ra03099g · Cited by 18
Delivery of mRNA for cancer therapy: progress and prospects
Su, L.-J., Xu, M.-X., Ji, Z.-H., Zhu, J.-Q., Yu, M., Wang, Y., & Lin, Y. (2023) · Nano Today · doi:10.1016/j.nantod.2023.102013 · Cited by 17
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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