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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]
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“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]
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“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
Sorted by citations
Lipid nanoparticles for mRNA delivery
Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00358-0 · Cited by 4,076
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
Lipids and Lipid Derivatives for RNA Delivery
Zhang, Y., Sun, C., Wang, C., Jankovic, K. E., & Dong, Y. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00244 · Cited by 649
mRNA vaccine delivery using lipid nanoparticles
Reichmuth, A. M., Oberli, M. A., Jaklenec, A., Langer, R., & Blankschtein, D. (2016) · Therapeutic Delivery · doi:10.4155/tde-2016-0006 · Cited by 624
Safety of Nanoparticles in Medicine
Wolfram, J., Zhu, M., Yang, Y. P., Shen, J., Gentile, E., Paolino, D., Fresta, M., Nie, G., Chen, C., Shen, H., et al. (2015) · Current Drug Targets · doi:10.2174/1389450115666140804124808 · Cited by 550
“Moreover, positively charged lipid nanoparticles injected into the blood were found to cause hepatotoxicity, which was evident from the increased presence of liver enzymes in the blood [107].”
BackgroundNanoparticle Hydrophobicity Dictates Immune Response
Moyano, D. F., Goldsmith, M., Solfiell, D. J., Landesman‐Milo, D., Miranda, O. R., Peer, D., & Rotello, V. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja2108905 · Cited by 479
Self-citationPiffoux, M., Silva, A., Wilhelm, C., Gazeau, F., & Tareste, D. C. (2018) · ACS Nano · doi:10.1021/acsnano.8b02053 · Cited by 474
Liposomal siRNA nanocarriers for cancer therapy
Özpolat, B., Sood, A. K., & Lopez‐Berestein, G. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2013.12.008 · Cited by 455
mRNA vaccine: a potential therapeutic strategy
Wang, Y., Zhang, Z., Luo, J., Han, X., Wei, Y., & Wei, X. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01311-z · Cited by 422
The Role of Surface Functionality in Determining Nanoparticle Cytotoxicity
Kim, S. T., Saha, K., Kim, C., & Rotello, V. M. (2013) · Accounts of Chemical Research · doi:10.1021/ar3000647 · Cited by 403
Targeting cancer with mRNA–lipid nanoparticles: key considerations and future prospects
Kon, E., Ad‐El, N., Hazan‐Halevy, I., Stotsky‐Oterin, L., & Peer, D. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00811-9 · Cited by 393
“thus preventing immediate inflammatory toxicities driven by cationic lipids 8 .”
BackgroundInfluentialSelf-citationImmunological and Toxicological Considerations for the Design of Liposomes
Inglut, C. T., Sorrin, A. J., Kuruppu, T., Vig, S., Cicalo, J., Ahmad, H., & Huang, H. (2020) · Nanomaterials · doi:10.3390/nano10020190 · Cited by 384
“Cationic liposomes also increased the amount of Th1 and Th17 cytokines by 10–24 fold at 2 h post‐injection [80].”
BackgroundAnticancer nanomedicine and tumor vascular permeability; Where is the missing link?
Taurin, S., Nehoff, H. L., & Greish, K. F. (2012) · Journal of Controlled Release · doi:10.1016/j.jconrel.2012.07.013 · Cited by 313
Delivery Aspects of CRISPR/Cas for in Vivo Genome Editing
Wilbie, D., Walther, J., & Mastrobattista, E. (2019) · Accounts of Chemical Research · doi:10.1021/acs.accounts.9b00106 · Cited by 311
Nanoparticles for Imaging, Sensing, and Therapeutic Intervention
Bogart, L. K., Pourroy, G., Murphy, C. J., Puntes, V., Pellegrino, T., Rosenblum, D., Peer, D., & Lévy, R. (2014) · ACS Nano · doi:10.1021/nn500962q · Cited by 303
Self-citationNanoparticle–blood interactions: the implications on solid tumour targeting
Lazarovits, J., Chen, Y. Y., Sykes, E. A., & Chan, W. C. W. (2014) · Chemical Communications · doi:10.1039/c4cc07644c · Cited by 297
Action and Reaction: The Biological Response to siRNA and Its Delivery Vehicles
Kanasty, R. L., Whitehead, K. A., Vegas, A. J., & Anderson, D. G. (2012) · Molecular Therapy · doi:10.1038/mt.2011.294 · Cited by 290
Circular RNA vaccine in disease prevention and treatment
Niu, D., Wu, Y., & Lian, J. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01561-x · Cited by 281
“161 160 – 162 LNP readily fuses with the target cell membrane.”
BackgroundRecent advances in mRNA-LNP therapeutics: immunological and pharmacological aspects
Kiaie, S. H., Zolbanin, N. M., Ahmadi, A., Bagherifar, R., Valizadeh, H., Kashanchi, F., & Jafari, R. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01478-7 · Cited by 269
“Using cationic lipids for in vivo administration demonstrated relative toxic effects due to high positive charge and poor endosomal escape [67].”
BackgroundNanomaterials in tumor immunotherapy: new strategies and challenges
Zhu, X., & Li, S. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01797-9 · Cited by 263
Recent advances in surface decoration of nanoparticles in drug delivery
Ly, P.-D., Ly, K.-N., Phan, H.-L., Nguyen, H. H. T., Duong, V., & Nguyen, H. V. (2024) · Frontiers in Nanotechnology · doi:10.3389/fnano.2024.1456939 · Cited by 265
Mizrahy, S., Raz, S. R., Hasgaard, M., Liu, H., Soffer-Tsur, N., Cohen, K., Dvash, R., Landesman‐Milo, D., Bremer, M. G. E. G., Moghimi, S. M., et al. (2011) · Journal of Controlled Release · doi:10.1016/j.jconrel.2011.06.031 · Cited by 259
“Preparation of NPs Multilamellar vesicles (MLV) composed of PC:Chol:DPPE at mole ratios of 15:4:1, were prepared by the traditional lipid-film method [10,11,20,21].”
MethodSelf-citationSmall interfering RNA for cancer treatment: overcoming hurdles in delivery
Charbe, N. B., Amnerkar, N. D., Ramesh, B., Tambuwala, M. M., Bakshi, H. A., Aljabali, A. A. A., Khadse, S. C., Satheeshkumar, R., Satija, S., Metha, M., et al. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.10.005 · Cited by 250
Biocompatibility and nanostructured materials: applications in nanomedicine
Adabi, M., Naghibzadeh, M., Adabi, M., Zarrinfard, M. A., Esnaashari, S. S., Seifalian, A. M., Majidi, R. F., Aiyelabegan, H. T., & Ghanbari, H. (2016) · Artificial Cells Nanomedicine and Biotechnology · doi:10.1080/21691401.2016.1178134 · Cited by 244
“On the other hand, cationic nanoparticles are much more potent in activation of immune response than neutral or anionic nanoparticles (Kedmi et al. 2010, Zolnik et al. 2010).”
BackgroundLipid Nanoparticles as Delivery Systems for RNA-Based Vaccines
Aldosari, B. N., Alfagih, I. M., & Almurshedi, A. S. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13020206 · Cited by 248
Strategies to reduce the risks of mRNA drug and vaccine toxicity
Bitounis, D., Jacquinet, E., Rogers, M. A., & Amiji, M. M. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00859-3 · Cited by 242
“Identification of pathogenicity is the event that initiates complement activation, of which there are three pathways: the classical pathway, initiated by pattern recognition by IgG or IgM; the alternative pathway, initiated by the hydrolysis of the thioester bond in complement protein C3; finally, the lectin pathway,…”
InfluentialSurface ligands in synthesis, modification, assembly and biomedical applications of nanoparticles
Ling, D., Hackett, M., & Hyeon, T. (2014) · Nano Today · doi:10.1016/j.nantod.2014.06.005 · Cited by 232
Cationic lipids activate intracellular signaling pathways
Lonez, C., Vandenbranden, M., & Ruysschaert, J.-M. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.05.009 · Cited by 221
“Finally, the fact that insertion of DOTAP into neutral liposomes lead to a larger cytokine release as compared to DOTAP alone [48,50,57] suggests that the modification of the cationic liposomes composition, by inserting cationic lipids into neutral liposomes, could be a way to regulate their immunostimulatory properti…”
BackgroundProgress and prospects of mRNA-based drugs in pre-clinical and clinical applications
Shi, Y., Shi, M., Wáng, Y., & You, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02002-z · Cited by 243
Chitosan Nanoparticles: A Versatile Platform for Biomedical Applications
Bashir, S. M., Rather, G. A., Patrício, A. B., Haq, Z., Sheikh, A. A., Shah, M. Z. U. H., Singh, H., Khan, A. A., Imtiyaz, S., Ahmad, S. B., et al. (2022) · Materials · doi:10.3390/ma15196521 · Cited by 230
Buyens, K., Smedt, S. C. D., Braeckmans, K., Demeester, J., Peeters, L., van Grunsven, L. A., du Jeu, X. D. M., Sawant, R. R., Torchilin, V. P., Farkasova, K., et al. (2011) · Journal of Controlled Release · doi:10.1016/j.jconrel.2011.10.009 · Cited by 207
Next-Generation Lipids in RNA Interference Therapeutics
Rietwyk, S., & Peer, D. (2017) · ACS Nano · doi:10.1021/acsnano.7b04734 · Cited by 199
Self-citationMerging the best of both worlds: hybrid lipid-enveloped matrix nanocomposites in drug delivery
Raemdonck, K., Braeckmans, K., Demeester, J., & Smedt, S. C. D. (2013) · Chemical Society Reviews · doi:10.1039/c3cs60299k · Cited by 192
Miyazawa, T., Itaya, M., Burdeos, G. C., Nakagawa, K., & Miyazawa, T. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s298606 · Cited by 198
“Kedmi et al prepared cationic charged surfactant-coated nanoparticles (small interfering RNA [siRNA] encapsulated in solid lipid nanoparticles coated with a cationic surfactant [1, 2-dioleoyl3-trimethylammonium-propane (DOTAP)]) and observed the activation of the innate immune system in C57BL/6 mice.(106) The results…”
MethodDesign and self-assembly of siRNA-functionalized RNA nanoparticles for use in automated nanomedicine
Afonin, K. A., Grabow, W. W., Walker, F. M., Bindewald, E., Dobrovolskaia, M. A., Shapiro, B. A., & Jaeger, L. (2011) · Nature Protocols · doi:10.1038/nprot.2011.418 · Cited by 182
“, our system applies the simplicity and biocompatibility unique to an all-RNA NP to package multiple siRNAs, thus eliminating the need to use sophisticated chemistry or materials, which can cause concerns with respect to toxicit”
MethodBhattacharjee, S., Rietjens, I. M. C. M., Singh, M. P., Atkins, T. M., Purkait, T. K., Xu, Z., Regli, S., Shukaliak, A. M., Clark, R. J., Mitchell, B. S., et al. (2013) · Nanoscale · doi:10.1039/c3nr34266b · Cited by 190
Nanoscale platforms for messenger RNA delivery
Li, B., Zhang, X., & Dong, Y. (2019) · WIREs Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1530 · Cited by 170
Shim, M. K., Park, J., Yoon, H. Y., Lee, S., Um, W., Kim, J.-H., Kang, S., Seo, J., Hyun, S., Park, J. H., et al. (2018) · Journal of Controlled Release · doi:10.1016/j.jconrel.2018.11.032 · Cited by 169
Martins, S., Lima, S. A. C., Carneiro, T., Cordeiro‐da‐Silva, A., Souto, E. B., & Ferreira, D. (2012) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2012.03.032 · Cited by 165
A SARS-CoV-2 targeted siRNA-nanoparticle therapy for COVID-19
Idris, A., Davis, A. M., Supramaniam, A., Acharya, D., Kelly, G., Tayyar, Y., West, N. P., Zhang, P., McMillan, C. L. D., Soemardy, C., et al. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.05.004 · Cited by 167
“34 By reducing the amount of DOTAP in our dmLNP-siRNAs, we have reduced the positive surface charge on the particles by approximately half compared to the sLNP-siRNAs.”
TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings
Boushehri, M. A. S., & Lamprecht, A. (2018) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.8b00691 · Cited by 163
Liu, M., Wang, Y., Zhang, Y.-B., Hu, D., Tang, L., Zhou, B., & Yang, L. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02112-8 · Cited by 189
Locatelli, E., Naddaka, M., Uboldi, C., Loudos, G. K., Fragogeorgi, E. A., Molinari, V., Pucci, A., Tsotakos, T., Psimadas, D., Ponti, J., et al. (2014) · Nanomedicine · doi:10.2217/nnm.14.1 · Cited by 158
Granot-Matok, Y., & Peer, D. (2017) · Seminars in Immunology · doi:10.1016/j.smim.2017.08.015 · Cited by 160
Self-citationMultifaceted Applications of Chitosan in Cancer Drug Delivery and Therapy
Babu, A., & Ramesh, R. (2017) · Marine Drugs · doi:10.3390/md15040096 · Cited by 154
Liu, S., Wen, Y., Shan, X., Ma, X., Yang, C., Cheng, X., Zhao, Y., Li, J., Mi, S., Huo, H., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53914-x · Cited by 168
“These results suggest that lungs may have a better tolerance to positively charged nanoparticles, which often arouse toxicity issues after systemic injections in clinical studies 26,27 .”
Perturbation of physiological systems by nanoparticles
Zhang, Y., Bai, Y., Jia, J., Gao, N., Li, Y., Zhang, R., Jiang, G., & Yan, B. (2014) · Chemical Society Reviews · doi:10.1039/c3cs60338e · Cited by 152
Special delivery: targeted therapy with small RNAs
Peer, D., & Lieberman, J. (2011) · Gene Therapy · doi:10.1038/gt.2011.56 · Cited by 152
Self-citationMartins, S. M., Sarmento, B. F. C. C., Nunes, C., Lúcio, M., Reis, S., & Ferreira, D. (2013) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2013.08.011 · Cited by 140
Altering the immune response with lipid-based nanoparticles
Landesman‐Milo, D., & Peer, D. (2011) · Journal of Controlled Release · doi:10.1016/j.jconrel.2011.12.034 · Cited by 141
“In contrast, an undesirable immuno-stimulation response may be caused by the interactionwith NPs with specific cell surface receptors on subsets of leukocytes [7,9,11,12] and can induce cytokine storm, interferon response and/or lymphocytes activation causing severe adverse effects that may diminish the therapeutic ef…”
BackgroundSelf-citationKnife’s edge: Balancing immunogenicity and reactogenicity in mRNA vaccines
Lee, J., Woodruff, M. C., Kim, E. H., & Nam, J. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-00999-x · Cited by 141
Chaudhary, N., Kasiewicz, L. N., Newby, A. N., Arral, M. L., Yerneni, S. S., Melamed, J. R., LoPresti, S. T., Fein, K. C., Petersen, D. M. S., Kumar, S., et al. (2024) · Nature Biomedical Engineering · doi:10.1038/s41551-024-01256-w · Cited by 153
Nanomaterials for Therapeutic RNA Delivery
Han, X., Mitchell, M. J., & Nie, G. (2020) · Matter · doi:10.1016/j.matt.2020.09.020 · Cited by 139
“Alternatively, to harness the proinflammatory effect, self-adjuvanting liposomes are being developed for mRNA vaccination.(39,40)”
BackgroundLipid-Based Nanoparticles in The Systemic Delivery of siRNA
Lin, Q., Chen, J., Zhang, Z., & Zheng, G. (2013) · Nanomedicine · doi:10.2217/nnm.13.192 · Cited by 133
Zeng, Q., Li, H., Jiang, H., Yu, J., Wang, Y., Ke, H., Gong, T., Zhang, Z., & Sun, X. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.01.010 · Cited by 133
Topal, G. R., Mészáros, M., Porkoláb, G., Szecskó, A., Polgár, T. F., Siklós, L., Deli, M. A., Veszelka, S., & Bozkır, A. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics13010038 · Cited by 133
“Negatively charged lipid NPs are generally less toxic and have higher stability compared to positively charged NPs [48].”
BackgroundPhysiological Barriers and Strategies of Lipid‐Based Nanoparticles for Nucleic Acid Drug Delivery
Hu, M., Li, X., You, Z., Cai, R., & Chen, C. (2023) · Advanced Materials · doi:10.1002/adma.202303266 · Cited by 142
Cationic lipid nanocarriers activate Toll-like receptor 2 and NLRP3 inflammasome pathways
Lonez, C., Bessodes, M., Scherman, D., Vandenbranden, M., Escriou, V., & Ruysschaert, J. (2013) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2013.12.003 · Cited by 129
“In contrast to what has been demonstrated and suggested for other cationic lipids [13, 30, 32], NF-κB activation by RPR206252 nanoparticles is not TLR4/MD2dependent but rather requires TLR2.”
ResultThe immunostimulatory nature of mRNA lipid nanoparticles
Sharma, P., Hoorn, D., Aitha, A., Breier, D., & Peer, D. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.115175 · Cited by 132
Self-citationOrtiz, A. C., Yáñez, O., Salas‐Huenuleo, E., & Morales, J. O. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13040531 · Cited by 135
“On the other hand, positive nanoparticles can activate faster immune responses than neutral or negative nanoparticles [50].”
BackgroundLiu, L., Yi, H., He, H., Pan, H., Cai, L., & Ma, Y. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.04.043 · Cited by 124
Precision medicine: In vivo CAR therapy as a showcase for receptor-targeted vector platforms
Michels, A., Ho, N., & Buchholz, C. J. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.05.018 · Cited by 131
Pro-inflammatory concerns with lipid nanoparticles
Moghimi, S. M., & Simberg, D. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.04.011 · Cited by 124
“Although these vaccines use N1-methyl-pseudour-idine-modi fi ed RNA (which is poorly recognizable by the Toll-like receptors 7/8), it is not clear how these vaccines elicit reactogenicity, but this presumably indicates that LNPs have intrinsic adjuvant activity.”
Quantification and real-time tracking of RNA in live cells using Sticky-flares
Briley, W. E., Bondy, M. H., Randeria, P. S., Dupper, T. J., & Mirkin, C. A. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510581112 · Cited by 121
“Proc Natl Acad Sci USA 94(10):5395–5400.”
BackgroundRothschild, S. I. (2014) · Molecular and Cellular Therapies · doi:10.1186/2052-8426-2-7 · Cited by 120
“It has been shown that systemic administration of positively charged lipid nanoparticles in vivo is toxic and stimulates inflammatory response by elevating both Th1 and Th17 cytokines and interferon responsive genes [79].”
BackgroundAdvances in Nanotechnology as They Pertain to Food and Agriculture: Benefits and Risks
Sadeghi, R., Rodriguez, R. J., Yao, Y., & Kokini, J. L. (2017) · Annual Review of Food Science and Technology · doi:10.1146/annurev-food-041715-033338 · Cited by 117
Ly, H. H., Daniel, S., Soriano, S. K. V., Kis, Z., & Blakney, A. K. (2022) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.2c00032 · Cited by 120
Nanoparticle Surface Functionality Dictates Cellular and Systemic Toxicity
Saei, A. A., Yazdani, M., Lohse, S. E., Bakhtiary, Z., Serpooshan, V., Ghavami, M., Asadian, M., Mashaghi, S., Dreaden, E. C., Mashaghi, A., et al. (2017) · Chemistry of Materials · doi:10.1021/acs.chemmater.7b01979 · Cited by 116
Chander, N., Basha, G., Cheng, M. H. Y., Witzigmann, D., & Cullis, P. R. (2023) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2023.06.005 · Cited by 117
“Unfortunately, such lipids can be toxic, potentially limiting clinical applications.(12,13)”
BackgroundNon-immunotherapy application of LNP-mRNA: Maximizing efficacy and safety
Vlatkovic, I. (2021) · Biomedicines · doi:10.3390/biomedicines9050530 · Cited by 112
Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions
Anchordoquy, T. J., Artzi, N., Balyasnikova, I. V., Barenholz, Y., La-Beck, N. M., Brenner, J. S., Chan, W. C. W., Decuzzi, P., Exner, A. A., Gabizón, A., et al. (2024) · ACS Nano · doi:10.1021/acsnano.4c00182 · Cited by 116
Self-citationAcid-degradable lipid nanoparticles enhance the delivery of mRNA
Zhao, S., Gao, K., Han, H., Stenzel, M., Yin, B., Song, H., Lawanprasert, A., Nielsen, J. E., Sharma, R. K., Arogundade, O. H., et al. (2024) · Nature Nanotechnology · doi:10.1038/s41565-024-01765-4 · Cited by 117
“In addition, LNPs exhibit high levels of toxicity, due to their cationic and ionizable lipids, and also persist in tissues for days to weeks 3 .”
BackgroundAbumanhal-Masarweh, H., da Silva, D., Poley, M., Zinger, A., Goldman, E., Krinsky, N., Kleiner, R., Shenbach, G., Schroeder, J. E., Shklover, J., et al. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.06.025 · Cited by 109
“Previous studies have shown that the amine headgroup interacts electrostatically with negatively charged lipids and glycans on the cancer cell membrane [44], or, alternatively, the amine headgroup may bind serum proteins that facilitate the trafficking of the particles to unspecific endocytic receptors on the cancer c…”
BackgroundIntranasal vaccine: Factors to consider in research and development
Xu, H., Cai, L., Hufnagel, S., & Cui, Z. (2021) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2021.121180 · Cited by 104
Design of a nanostructured lipid carrier intended to improve the treatment of tuberculosis
Pinheiro, M., Ribeiro, R., Vieira, A. C. C., Andrade, F., & Reis, S. (2016) · Drug Design Development and Therapy · doi:10.2147/dddt.s104395 · Cited by 105
Overview on experimental models of interactions between nanoparticles and the immune system
Najafi-Hajivar, S., Zakeri‐Milani, P., Mohammadi, H., Niazi, M., Soleymani-Goloujeh, M., Baradaran, B., & Valizadeh, H. (2016) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2016.08.060 · Cited by 106
The Progress and Promise of RNA Medicine─An Arsenal of Targeted Treatments
Sasso, J. M., Ambrose, B. J. B., Tenchov, R., Datta, R. S., Basel, M. T., DeLong, R. K., & Zhou, Q. A. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00024 · Cited by 108
Modulation of Immune Response Using Engineered Nanoparticle Surfaces
Moyano, D. F., Liu, Y., Peer, D., & Rotello, V. M. (2015) · Small · doi:10.1002/smll.201502273 · Cited by 107
Self-citationZhang, R., Tang, L., Tian, Y., Xiao, J., Hu, Q., Zhou, B., Ding, Z., Xu, H., & Yang, L. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.08.023 · Cited by 101
Zelkoski, A. E., Lu, Z., Sukumar, G., Dalgard, C. L., Said, H., Alameh, M., Mitre, E. E. S., & Malloy, A. M. W. (2025) · npj Vaccines · doi:10.1038/s41541-025-01124-x · Cited by 117
“SomecationicLNPscanbedetectedby TLR4 and the NLRP3 in fl ammasome 25,27 – 31 .”
Mahmoud, K. Y., Swidan, S. A., El-Nabarawi, M. A., & Teaima, M. H. M. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01309-9 · Cited by 106
Reshaping the Future of Nanopharmaceuticals: Ad Iudicium
Moghimi, S. M., Peer, D., & Langer, R. (2011) · ACS Nano · doi:10.1021/nn2038252 · Cited by 104
Self-citationNanoparticle-mediated Gene Silencing Confers Radioprotection to Salivary Glands In Vivo
Arany, S., Benoit, D. S. W., Dewhurst, S., & Ovitt, C. E. (2013) · Molecular Therapy · doi:10.1038/mt.2013.42 · Cited by 97
A single-dose F1-based mRNA-LNP vaccine provides protection against the lethal plague bacterium
Kon, E., Levy, Y., Elia, U., Cohen, H., Hazan‐Halevy, I., Aftalion, M., Ezra, A., Bar‐Haim, E., Naidu, G. S., Diesendruck, Y., et al. (2023) · Science Advances · doi:10.1126/sciadv.adg1036 · Cited by 97
“…of SP-cp-caf1 mRNA-LNPs, we hypothesized that incorporation of 1,2-Dioleoyl-3-trimethylammo-nium propane (DOTAP), a cationic lipid that induces strong immediate inflammatory responses via innate signaling, in the LNPs formulation might elicit humoral response in vaccinated animals ( 26 ).”
Self-citationNon-viral nanocarriers for siRNA delivery in breast cancer
Zhang, J., Li, X., & Huang, L. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.05.037 · Cited by 99
Saha, K., Bajaj, A., Duncan, B., & Rotello, V. M. (2011) · Small · doi:10.1002/smll.201100478 · Cited by 97
Zhang, C., Ma, Y., Zhang, J., Kuo, J. C., Zhang, Z., Xie, H., Zhu, J., & Liu, T. (2022) · Molecules · doi:10.3390/molecules27061943 · Cited by 95
Algarni, A., Pilkington, E. H., Suys, E. J. A., Al-Wassiti, H. A., Pouton, C. W., & Truong, N. P. (2022) · Biomaterials Science · doi:10.1039/d2bm00168c · Cited by 95
Advanced subunit vaccine delivery technologies: From vaccine cascade obstacles to design strategies
Hou, Y., Chen, M., Bian, Y., Zheng, X., Tong, R., & Sun, X. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.01.006 · Cited by 100
Greish, K. F. (2011) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2011.11.010 · Cited by 92
siRNA Delivery: From Lipids to Cell‐penetrating Peptides and Their Mimics
Gooding, M., Browne, L., Quinteiro, F. M., & Selwood, D. L. (2012) · Chemical Biology & Drug Design · doi:10.1111/cbdd.12052 · Cited by 91
Liu, Y., Gunda, V., Zhu, X., Xu, X., Wu, J., Askhatova, D., Farokhzad, O. C., Parangi, S., & Shi, J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1605841113 · Cited by 90
“Given the potential immunogenic response associated with NPs with highly positive charges (21), we selected the NP formulation with a lower positive charge but a favorable in vitro silencing effect (NP#2) for the following in vivo experiments unless otherwise specified.”
BackgroundNanotechnology-Based Strategies to Overcome Current Barriers in Gene Delivery
Mirón-Barroso, S., Domènech, E. B., & Trigueros, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168537 · Cited by 91
“The positively charged surface consequently prompts the recognition and uptake of these systems by phagocytic cells and results in activation of the immune response [62].”
BackgroundAdjuvant physiochemistry and advanced nanotechnology for vaccine development
Ren, H., Jia, W., Xie, Y., Yu, M., & Chen, Y. (2023) · Chemical Society Reviews · doi:10.1039/d2cs00848c · Cited by 91
Vieira, A. C. C., Magalhães, J., Rocha, S., Cardoso, M. S., Santos, S. G., Borges, M. C., Pinheiro, M., & Reis, S. (2017) · Nanomedicine · doi:10.2217/nnm-2017-0248 · Cited by 89
Immunotoxicity derived from manipulating leukocytes with lipid-based nanoparticles
Peer, D. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.06.013 · Cited by 88
“In contrast, robust immune stimulation might cause an undesirable response, for example, when lipid-based nanoparticles (LNPs) interactwith specific cell surface receptors on subsets of leukocytes [1,10,13,14] and can induce cytokine storm, interferon response and/or lymphocyte activation causing severe adverse effect…”
BackgroundInfluentialSelf-citationCohen, K., Emmanuel, R., Kisin‐Finfer, E., Shabat, D., & Peer, D. (2014) · ACS Nano · doi:10.1021/nn500205b · Cited by 85
Self-citation
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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