Cited by 546RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryImmune Response and Inflammation

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

Kedmi, Ranit, Ben-Arie, Noa, Peer, Dan·2010·Biomaterials

DOI 10.1016/j.biomaterials.2010.05.027

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1016/j.biomaterials.2010.05.027

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

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
Inflammation and cancer
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
On the nature of biomaterials
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

Show all 52 references

Sorted by citations

Items 301–400 of 544

Encapsulation of camptothecin into pegylated polyelectrolyte nanocarriers
Bzowska, M., Karabasz, A., & Szczepanowicz, K. (2018) · Colloids and Surfaces A Physicochemical and Engineering Aspects · doi:10.1016/j.colsurfa.2018.05.070 · Cited by 17
Cell-based high-throughput screening of cationic polymers for efficient DNA and siRNA delivery
Wu, Y., Wang, L., Xiong, Y., Zhou, Q., Li, L. X., Chen, G., Ping, Y., Davidson, G. R., Levkin, P. A., Gao, L., et al. (2020) · Acta Biomaterialia · doi:10.1016/j.actbio.2020.08.029 · Cited by 17
Polymer design and component selection contribute to uptake, distribution & trafficking behaviours of polyethylene glycol hyperbranched polymers in live MDA-MB-468 breast cancer cells
Simpson, J. D., Ediriweera, G. R., Howard, C. B., Fletcher, N. L., Bell, C. A., & Thurecht, K. J. (2019) · Biomaterials Science · doi:10.1039/c9bm00957d · Cited by 17
Permanently Charged Cationic Lipids—Evolution from Excipients to Therapeutic Lipids
Pushpa Ragini, S., Banerjee‬‬‬‬‬‬‬‬‬, R., Drummond, C. J., & Conn, C. E. (2024) · Small Science · doi:10.1002/smsc.202300270 · Cited by 17
Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics
Yuen, J. G., Fesler, A. T., Hwang, G., Chen, L.-B., & Ju, J. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.07.015 · Cited by 17
Toll-like receptor-targeted nanoparticles: A powerful combination for tumor immunotherapy
Zhi, X., Yang, P., Xu, Y., Dai, Z., Yue, X., & Qian, L. (2023) · Nano Today · doi:10.1016/j.nantod.2023.102003 · Cited by 17
Osteoporosis therapy using nanoparticles: a review
Zeghoud, S., Amor, I. B., Alhamad, A. A., Darwish, L. R., & Hemmami, H. (2023) · Annals of Medicine and Surgery · doi:10.1097/ms9.0000000000001467 · Cited by 16
“They can improve therapeutic loading, increase tissue selectivity, and decrease dosages without compromising therapy ef ﬁ cacy because of their capacity to be chemically changed [44] .”
Background
Cell-Specific mRNA Therapeutics for Cardiovascular Diseases and Regeneration
Kishore, R., & Magadum, A. (2024) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd11020038 · Cited by 17
“While excessive immune reactions are undesirable, controlled immune response activation can be advantageous in RNA-LNP-based vaccines [61].”
Background
Enhanced brain delivery with lower hepatic exposure of lazaroid loaded nanostructured lipid carriers developed using a design of experiment approach
Gadgil, P., Shah, J., & Chow, D. S. (2018) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2018.04.046 · Cited by 16
Synergistic effect of reduced polypeptide micelle for co-delivery of doxorubicin and TRAIL against drug-resistance in breast cancer
Hu, C., Gu, F., Tai, Z., Yao, C., Gong, C., Xia, Q., Gao, Y., & Gao, S. (2016) · Oncotarget · doi:10.18632/oncotarget.11451 · Cited by 16
“Body weight change was used an indicator of systemic toxicity (Figure 7C) [34, 35].”
Method
Next-generation poly-L-histidine formulations for miRNA mimic delivery
Kasina, V., Wahane, A. V., Liu, C., Yang, L., Nieh, M., Slack, F. J., & Bahal, R. (2023) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2023.03.015 · Cited by 15
“However, there are challenges, as highly cationic delivery systems are known to cause systemic toxicity in vivo.(37) Delivery systems with modest positive charges would reduce potential toxicity.”
Background
Advances of Nanotechnology Toward Vaccine Development Against Animal Infectious Diseases
Wang, X., Gao, X., Wang, L., Lin, J., & Liu, Y. (2023) · Advanced Functional Materials · doi:10.1002/adfm.202305061 · Cited by 16
mRNA biotherapeutics landscape for rare genetic disorders
Iyer, V. R., Praveen Reddy., P., Kaduskar, B., Moharir, S. C., & Mishra, R. K. (2024) · Journal of Biosciences · doi:10.1007/s12038-023-00415-6 · Cited by 17
“2003; Dass 2004; Kedmi et al .”
Head on Comparison of Self‐ and Nano‐Assemblies of Gamma Peptide Nucleic Acid Amphiphiles
Malik, S., Kumar, V., Liu, C., Shih, K., Krueger, S., Nieh, M., & Bahal, R. (2021) · Advanced Functional Materials · doi:10.1002/adfm.202109552 · Cited by 16
Nanotoxicity and the importance of being earnest
Vorup‐Jensen, T., & Peer, D. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.09.002 · Cited by 15
“In addition to complement activation, other parts of the innate immune system also contribute to adverse immune response to nanomedicine formulations [21].”
BackgroundSelf-citation
Design and Evaluation of Thioalkylated Mannose-Modified Dendrimer (G3)/α-Cyclodextrin Conjugates as Antigen-Presenting Cell-Selective siRNA Carriers
Motoyama, K., Mitsuyasu, R., Akao, C., Tanaka, T., Ohyama, A., Sato, N., Higashi, T., & Arima, H. (2014) · The AAPS Journal · doi:10.1208/s12248-014-9665-9 · Cited by 15
Effects of Immune Cell Heterogeneity and Protein Corona on the Cellular Association and Cytotoxicity of Gold Nanoparticles: A Single-Cell-Based, High-Dimensional Mass Cytometry Study
Park, S., Ha, M. K., Lee, Y., Song, J., & Yoon, T. H. (2023) · ACS Nanoscience Au · doi:10.1021/acsnanoscienceau.3c00001 · Cited by 14
Effect of the amount of cationic lipid used to complex siRNA on the cytotoxicity and proinflammatory activity of siRNA-solid lipid nanoparticles
Hanafy, M. S., Dao, H. M., Xu, H., Koleng, J. J., Sakran, W., & Cui, Z. (2023) · International Journal of Pharmaceutics X · doi:10.1016/j.ijpx.2023.100197 · Cited by 14
“higher proinflammatory cytokine production (Kedmi et al., 2010).”
Recent Advances in Messenger Ribonucleic Acid (mRNA) Vaccines and Their Delivery Systems: A Review
Belay, W. Y., Nibret, G., & Aschale, Y. (2023) · Clinical Pharmacology Advances and Applications · doi:10.2147/cpaa.s418314 · Cited by 16
Dual-mRNA Delivery Using Tumor Cell Lysate-Based Multifunctional Nanoparticles as an Efficient Colon Cancer Immunogene Therapy
Wang, K., Gao, Y., Wu, S., Zhang, J., Zhu, M., Chen, X., Fu, X., Duan, X., & Men, K. (2024) · International Journal of Nanomedicine · doi:10.2147/ijn.s452548 · Cited by 14
Analysis of human innate immune responses to PRINT fabricated nanoparticles with cross validation using a humanized mouse model
Robbins, G. R., Roberts, R. A., Guo, H., Reuter, K., Shen, T. W., Sempowski, G. D., McKinnon, K. P., Su, L., DeSimone, J. M., & Ting, J. P. ‐. (2015) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2014.11.010 · Cited by 14
“The nanotechnology field is continually expanding and encompasses a variety of materials, some of which are reported to induce toxicity and/or adverse immune responses, including metals, metal oxides, carbon-nanotubes, liposomes and some polymer based particles.(10,11,18) A drawback of many therapeutic platforms is th…”
Cargo-free particles of ammonio methacrylate copolymers: From pharmaceutical inactive ingredients to effective anticancer immunotherapeutics
Boushehri, M. A. S., Stein, V., & Lamprecht, A. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.02.053 · Cited by 14
Comparing nanoparticles for drug delivery: The effect of physiological dispersion media on nanoparticle properties
Ross, A. M., Kennedy, T., McNulty, D., Leahy, C. I., Walsh, D. R., Murray, P. G., Grabrucker, A. M., & Mulvihill, J. J. (2020) · Materials Science and Engineering C · doi:10.1016/j.msec.2020.110985 · Cited by 14
The offset effect of a hyaluronic acid coating to cationic carriers containing siRNA: Alleviated cytotoxicity and retained gene silencing in vitro
Fukushige, K., Tagami, T., & Ozeki, T. (2017) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2017.03.024 · Cited by 14
Targeted Drug Delivery to the Spleen and Its Implications for the Prevention and Treatment of Cancer
Khalil, I. A., Faheem, A., & El‐Tanani, M. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17050651 · Cited by 15
“Several independent studies have shown that positively charged systems were more effectively delivered to the spleen [54–56].”
Versatile Cell Penetrating Peptide for Multimodal CRISPR Gene Editing in Primary Stem Cells
Graham, J. P., Castro, J. G., Werba, L. C., Amitrano, J., Fardone, L. C., Francis, K. P., Ramamurthi, A., Layden, M. J., McCarthy, H. O., & Gonzalez‐Fernandez, T. (2025) · Advanced Functional Materials · doi:10.1002/adfm.202501532 · Cited by 15
“However, many commercial lipid vectors still have cytotoxic effects on transfected cells, leading to transcriptomic dysregulation that results in cell death and the disruption of stem cell’s differentiation and proliferation capacity [27, 28, 29].”
A microphysiological system for screening lipid nanoparticle−mRNA complexes predicts in vivo heart transfection efficacy
Neiman, G., Costa, M. W., Han, H., Zhao, S., Ng, T. K., Siemons, B. A., Nishino, T., Huang, Y., Jinagal, S. L., Wu, K., et al. (2025) · Nature Biomedical Engineering · doi:10.1038/s41551-025-01523-4 · Cited by 15
“One of the main concerns for LNPs is their clinical safety, since it is widely known that cationic lipids are inherently toxic at high concentrations and can affect the normal function of the target organ 29,30 .”
The optimization strategies of LNP-mRNA formulations: Development and challenges for further application
Wang, S., Guo, B., Wang, H., & Yang, F. (2024) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2024.105547 · Cited by 14
Encapsulation of Citrus sinensis essential oil and R-limonene in lipid nanocarriers: A potential strategy for the treatment of leishmaniasis
dos Santos, J. D. S., Galvão, J. G., Mendonça, M. R. D. C., Costa, A. M., Silva, A. R. S. T., Oliveira, D. S., Santos, A. D. J., Lira, A. A. M., Scher, R., Sales, P. A., et al. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.124464 · Cited by 13
Status Quo in the Liposome-Based Therapeutic Strategies Against Glioblastoma: “Targeting the Tumor and Tumor Microenvironment”
Haseeb, M., Khan, I., Kartal, Z., Mahfooz, S., & Hatiboğlu, M. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252011271 · Cited by 14
“Kedmi et al. [189] studied various aspects of liposomal toxicity, such as hepatotoxicity and inflammatory responses, using in vivo animal models.”
Tailor-made curdlan based nanofibrous dressings enable diabetic wound healing
Chen, Y., Bera, H., Si, L., Xiu, F., Liu, P., Li, J., Xu, X., Zhu, X., Li, Y., Cun, D., et al. (2024) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2024.122876 · Cited by 12
Nanoparticles as immunomodulators and translational agents in brain tumors
Grippin, A., Dyson, K. A., Qdaisat, S., McGuiness, J., Wummer, B. M., Mitchell, D. A., Méndez‐Gómez, H. R., & Sayour, E. J. (2020) · Journal of Neuro-Oncology · doi:10.1007/s11060-020-03559-9 · Cited by 13
Acid‐Responsive Polymer Additives Increase RNA Transfection from Lipid Nanoparticles
Cheung, T. H., Fuchs, A., & Shoichet, M. S. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202413220 · Cited by 13
Cascade‐Targeted Nanoparticles for Enhanced Gemcitabine Delivery and Adenosine Metabolism Modulation to Overcome Treatment Resistance in Pancreatic Cancer
Fan, H., Chen, H., Song, H., Li, C., Wang, Y., Zhao, Z., Guo, Q., Li, X., Liu, M., Sun, T., et al. (2025) · Advanced Science · doi:10.1002/advs.202507118 · Cited by 13
Non-viral delivery of RNA for therapeutic T cell engineering
Berdecka, D., Smedt, S. C. D., Vos, W. H. D., & Braeckmans, K. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115215 · Cited by 14
The application strategy of liposomes in organ targeting therapy
Xun, Z., Li, T., & Xue, X. (2024) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1955 · Cited by 12
Сationic liposomes as delivery systems for nucleic acids
Mikheev, A. A., Shmendel, E. V., Zhestovskaya, E. S., Nazarov, G. V., & Maslov, M. A. (2020) · Fine Chemical Technologies · doi:10.32362/2410-6593-2020-15-1-7-27 · Cited by 12
Focus on RNA interference: from nanoformulations to in vivo delivery
Karp, J. M., & Peer, D. (2017) · Nanotechnology · doi:10.1088/1361-6528/aa98e3 · Cited by 12
Self-citation
Hepatocyte-Targeted Delivery of siRNA Polyplex with PEG-Modified Lactosylated Dendrimer/Cyclodextrin Conjugates for Transthyretin-Related Amyloidosis Therapy
Hayashi, Y., Higashi, T., Motoyama, K., Jono, H., Ando, Y., Onodera, R., & Arima, H. (2019) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b19-00278 · Cited by 12
Immunoactive drug carriers in cancer therapy
Meng, F., Kwon, S., Wang, J., & Yeo, Y. (2020) · Elsevier eBooks · doi:10.1016/b978-0-08-102983-1.00003-x · Cited by 13
Adjuvant potency of Astragaloside VII embedded cholesterol nanoparticles for H3N2 influenza vaccine
Genç, R., Yakuboğulları, N., Nalbantsoy, A., Çöven, F., & Bedіr, E. (2020) · TURKISH JOURNAL OF BIOLOGY · doi:10.3906/biy-2003-49 · Cited by 12
“LNPs have been developed to deliver immunostimulatory agents such as CpG [Toll Like Receptor (TLR-9) agonist] (Shirota and Klinman, 2014), MPL (monophosphoryl lipid A, TLR-4 agonist) (Kedmi et al., 2010), and small-molecule immune potentiators targeting TLR-7 (Wu et al., 2014).”
Background
Two quality and stability indicating imaged CIEF methods for mRNA vaccines
Krebs, F., Burger, U., Doerks, S., Krämer, M., & Wätzig, H. (2022) · Electrophoresis · doi:10.1002/elps.202200123 · Cited by 14
Polyplex Nanomicelle‐Mediated Pgc‐1α4 mRNA Delivery Via Hydrodynamic Limb Vein Injection Enhances Damage Resistance in Duchenne Muscular Dystrophy Mice
Du, X., Nakanishi, H., Yamada, T., Sin, Y., Minegishi, K., Motohashi, N., Aoki, Y., & Itaka, K. (2025) · Advanced Science · doi:10.1002/advs.202409065 · Cited by 11
Unlocking mRNA-driven CRISPR-Cas9 gene therapy via optimizing mRNA and the delivery vectors
Wang, S., Xu, X., Viitala, T., Shu, Y., & Zhang, H. (2025) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2025.102737 · Cited by 14
“169,170 In order to bypass these challenges, ionizable cationic lipids have been widely investigated for mRNA delivery.”
Development of a 5-FU modified miR-129 mimic as a therapeutic for non-small cell lung cancer
Hwang, G., Yuen, J. G., Fesler, A. T., Farley, H., Haley, J. D., & Ju, J. (2023) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2023.02.007 · Cited by 11
“The inherent toxicity and unforeseen side effects of some delivery vehicles have been an obstacle in the effective delivery of RNA-based therapeutics.(36,72,73) Several studies have demonstrated the therapeutic potential of chemical modifications on miRNAs and siRNAs to overcome this obstacle, including the approval o…”
Background
Nose-to-brain drug delivery for the treatment of glioblastoma multiforme: nanotechnological interventions
Kumar, N., Khurana, B., & Arora, D. (2023) · Pharmaceutical Development and Technology · doi:10.1080/10837450.2023.2285506 · Cited by 12
“…NPs showed higher levels of liver enzymes, bodyweight loss suggesting hepatotoxicity, increased levels of pro-inflammatory mediators, and activation of TLR4 receptors responsible for an immune response when compared with Mice treated with negative and neutral nanoparticles (Kedmi et al. 2010).”
Background
Development of PET Radioisotope Copper-64-Labeled Theranostic Immunoliposomes for EGFR Overexpressing Cancer-Targeted Therapy and Imaging
Jeong, H. Y., Kang, S. J., Kim, M. W., Jeong, I., Choi, M. J., Jung, C., Song, I. H., Lee, T. S., & Park, Y. S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031813 · Cited by 11
“However, these positively charged lipids can be cytotoxic and lead to non-speciﬁc binding due to the membrane charge of liposomes [13–24].”
Background
Amphiphilic dynamic covalent polymer vectors of siRNA
Coll, J. G., Trousselier, P., Pawar, S. D., Bessin, Y., Lichon, L., Chain, J. L., Sachon, E., Bettache, N., & Ulrich, S. (2024) · Chemical Science · doi:10.1039/d4sc07668k · Cited by 11
Monitoring the Environmental Impact of TiO$_{\bf 2}$ Nanoparticles Using a Plant-Based Sensor Network
Lenaghan, S. C., Li, Y., Zhang, H., Burris, J. N., Stewart, C. N., Parker, L. E., & Zhang, M. (2013) · IEEE Transactions on Nanotechnology · doi:10.1109/tnano.2013.2242089 · Cited by 11
Providing The Full Picture: A Mandate for Standardizing Nanoparticle-Based Drug Delivery
Howard, K. A., & Peer, D. (2013) · Nanomedicine · doi:10.2217/nnm.13.95 · Cited by 11
Self-citation
Rapid Production of Human VEGF-A following Intradermal Injection of Modified VEGF-A mRNA Demonstrated by Cutaneous Microdialysis in the Rabbit and Pig In Vivo
Pehrsson, S., Hölttä, M., Linhardt, G., Danielson, R. F., & Carlsson, L. G. (2019) · BioMed Research International · doi:10.1155/2019/3915851 · Cited by 11
Applications and challenges of biomaterial mediated mRNA delivery
Fang, H., & Chen, Q. (2022) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2022.00093 · Cited by 12
Lipid/copolymer hybrid drug delivery systems: From design to performance
Triantafyllopoulou, E., Selianitis, D., Chountoulesi, M., Karayianni, M., Valsami, G. N., Pispas, S., & Pippa, Ν. (2026) · Advances in Colloid and Interface Science · doi:10.1016/j.cis.2026.103884 · Cited by 10
Alendronate/lactoferrin-dual decorated lipid nanocarriers for bone-homing and active targeting of ivermectin and methyl dihydrojasmonate for leukemia
Abou-Elnour, F. S., El-Habashy, S. E., Essawy, M. M., & Abdallah, O. Y. (2024) · Biomaterials Advances · doi:10.1016/j.bioadv.2024.213924 · Cited by 10
COVID‐19 vaccine adverse events: Evaluating the pathophysiology with an emphasis on sulfur metabolism and endotheliopathy
du Preez, H. N., Lin, J., Maguire, G. E. M., Aldous, C. M., & Kruger, H. G. (2024) · European Journal of Clinical Investigation · doi:10.1111/eci.14296 · Cited by 12
“256,257 It is also probable that overexpression of IFN in the heart can lead to autoimmune cardiomyopathy.”
Influential
Lipid Nanoparticles and PEG: Time Frame of Immune Checkpoint Blockade Can Be Controlled by Adjusting the Rate of Cellular Uptake of Nanoparticles
Choi, A. S., Moon, T. J., Bhalotia, A., Rajan, A., Ogunnaike, L., Hutchinson, D. W., Hwang, I., Gokhale, A., Kim, J. N., Ma, T., et al. (2025) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.4c01039 · Cited by 11
Silane and amino acid functionalized PBAEs for enhanced gene Delivery: Synthesis, characterization, and transfection efficiency
Kaplan, Ö., Bal, K., Şentürk, S., Demir, K., & Gök, M. K. (2025) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2025.106990 · Cited by 10
Nanoinformatics in Drug Delivery
Sason, H., & Shamay, Y. (2019) · Israel Journal of Chemistry · doi:10.1002/ijch.201900042 · Cited by 10
pH-sensitive, tail-modified, ester-linked ionizable cationic lipids for gene delivery
Zou, Y., Zhen, Y., Zhao, Y., Chen, H., Wang, R., Wang, W., Ma, P., Zhi, D., Ju, B., & Zhang, S. (2022) · Biomaterials Advances · doi:10.1016/j.bioadv.2022.212984 · Cited by 10
Ionizable Lipid with Supramolecular Chemistry Features for RNA Delivery In Vivo
Manning, A. M., Tilstra, G., Khan, A. B., Couture‐Senécal, J., Lau, Y. M. A., Pang, J., Abow, A. A., Robbins, C. S., & Khan, O. F. (2023) · Small · doi:10.1002/smll.202302917 · Cited by 10
Advances in the Formulation and Assembly of Non-Cationic Lipid Nanoparticles for the Medical Application of Gene Therapeutics
Fisher, R. K., West, P. C., Mattern‐Schain, S. I., Best, M. D., Kirkpatrick, S. S., Dieter, R. A., Arnold, J. D., Buckley, M. R., McNally, M. M., Freeman, M. B., et al. (2021) · Nanomaterials · doi:10.3390/nano11030825 · Cited by 10
“However, many synthetic, “unnatural” cationic lipids are associated with cytotoxicity through toll-like receptor activation [8], mitochondrial membrane disruption [9] and induction of reactive oxygen species [10].”
Background
Regulatory perspective for quality evaluation of lipid nanoparticle-based mRNA vaccines in China
Lu, J., Wei, W., & He, W. (2023) · Biologicals · doi:10.1016/j.biologicals.2023.101700 · Cited by 9
Silk Fibroin-Modified Liposome/Gene Editing System Knocks out the PLK1 Gene to Suppress the Growth of Lung Cancer Cells
Pan, P., Liu, X., Fang, M., Yang, S., Zhang, Y., Li, M., & Liu, Y. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15122756 · Cited by 9
“High charge density is one of the main reasons for the cytotoxicity of liposomes [60,61].”
Background
Lipid-based Drug Delivery Systems: A Promising Approach for Overcoming Bioavailability and Solubility Challenges in Drug Development
Gupta, A., Mittal, V., Sharma, A., Barak, A., & Arora, D. (2024) · Current Nanomedicine · doi:10.2174/0124681873290199240424062503 · Cited by 9
Advances in Liposomal Interleukin and Liposomal Interleukin Gene Therapy for Cancer: A Comprehensive Review of Preclinical Studies
Kubbara, E. A., Bolad, A. K., & Malibary, H. M. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17030383 · Cited by 10
“Further insights into liposomal toxicity were provided by Kedmi et al. [102], who investigated hepatotoxicity and inflammatory responses using in vivo animal models.”
Modification of Porous Silicon with an Amphiphilic Quaternary Ammonium Hydrocarbon for Nanomedicine Applications
Yang, Q., Zhou, M. Y., Stark, G. M., Fan, R., & Sailor, M. J. (2025) · Chemistry of Materials · doi:10.1021/acs.chemmater.5c01583 · Cited by 9
Live long and active: Polypeptide-mediated assembly of antibody variable fragments
Lee, C., Choi, M., & MacKay, J. A. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.10.017 · Cited by 11
“They also induced 15– 25-fold higher mRNAs of interferon responsive genes, and 10– 75-fold higher expression of pro inflammatory cytokines compared to negatively-charged or neutral nanoparticles [150].”
Background
Synthesis of sulfanyl porphyrazines with bulky peripheral substituents – Evaluation of their photochemical properties and biological activity
Falkowski, M., Kucińska, M., Piskorz, J., Wieczorek-Szweda, E., Popenda, Ł., Jurga, S., Sikora, A., Młynarczyk, D. T., Murias, M., Marszałł, M. P., et al. (2020) · Journal of Photochemistry and Photobiology A Chemistry · doi:10.1016/j.jphotochem.2020.112964 · Cited by 9
SARS-CoV-2 Vaccination and the Multi-Hit Hypothesis of Oncogenesis
Angues, R. V., & Bustos, Y. P. (2023) · Cureus · doi:10.7759/cureus.50703 · Cited by 11
“A recent report [150] specifically showed that the LNPs used in preclinical nucleoside-modified mRNA COVID-19 vaccine studies are highly inflammatory in mice.”
Background
Treatment of Francisella infections via PLGA- and lipid-based nanoparticle delivery of antibiotics in a zebrafish model
Ulanova, L. S., Pinheiro, M., Vibe, C. B., Nunes, C., Misaghian, D., Wilson, S., Zhu, K., Fenaroli, F., Winther-Larsen, H. C., Reis, S., et al. (2017) · Diseases of Aquatic Organisms · doi:10.3354/dao03129 · Cited by 9
“All synthesized NPs possessed a negative surface charge, an advantage since these are generally less toxic than NPs with a positive charge (Kedmi et al. 2010).”
Background
Macrophages: First Innate Immune Responders to Nanomaterials
You, D. J., Lee, H. Y., & Bonner, J. C. (2020) · Molecular and integrative toxicology · doi:10.1007/978-3-030-33962-3_2 · Cited by 9
Development of an extended action fostemsavir lipid nanoparticle
Islam, F. S., Das, S., Ashaduzzaman, M., Sillman, B., Yeapuri, P., Nayan, M. U., Oupický, D., Gendelman, H. E., & Kevadiya, B. D. (2024) · Communications Biology · doi:10.1038/s42003-024-06589-5 · Cited by 8
Emerging Cationic Nanovaccines
Carmona‐Ribeiro, A. M., & Pérez-Betancourt, Y. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16111362 · Cited by 8
“Additionally, the interaction of cationic NPs with immune cells can lead to the activation of various toll-like receptors (TLRs), which play a critical role in the innate immune system [59,85].”
Therapeutic potential of siRNA PMP22-SQ nanoparticles for Charcot-Marie-Tooth 1A neuropathy in rodents and non-human primates
Boutary, S., Khalaf, G., Landesman, Y., Madani, M. E., Desmaële, D., Piguet, F., Alonso, R., Banchi, E.-G., Adams, D., Massaad, C., et al. (2025) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2025.125234 · Cited by 8
Therapeutic Application of mRNA for Genetic Diseases
Schürmann, P. J. L., Vriesman, S. V. B., Castro-Alpízar, J., Kooijmans, S. A. A., Nieuwenhuis, E. E. S., Schiffelers, R. M., & Fuchs, S. A. (2025) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.70019 · Cited by 9
“Conversely, positively charged LNPs may disrupt cellular membranes, leading to cytotoxicity (Kedmi et al. 2010).”
Concerns and challenges in clinics-guided nanovaccines design and applications
Gao, Y., Hua, S., Dong, X., Zhang, K., Zhang, X., & Yang, J. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.10.041 · Cited by 8
“Research indicates that mice treated with cationic nanoparticles demonstrate increased hepatic enzyme release and weight loss compared to those treated with neutral or anionic nanoparticles 75 .”
Inflammatory and immune-mediated toxicity of lipid nanoparticles
Kim, S., Park, C., Lee, Y., Lee, K., Lee, H., & Lee, K. (2026) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2026.119385 · Cited by 8
Tumor Vasculature, EPR Effect, and Anticancer Nanomedicine: Connecting the Dots
Taurin, S., Nehoff, H. L., van Aswegen, T., & Greish, K. F. (2013) · Springer eBooks · doi:10.1007/978-1-4614-7876-8_8 · Cited by 8
“The innate elements of the immune system could be stimulated nonspecifi cally by these foreign bodies through TLR-4 [ 155 ].”
Cancer nutritional-immunotherapy with NIR-II laser-controlled ATP release based on material repurposing strategy
Lu, J., Wang, Y., Gao, X., Li, Y., Neema, U.-P., Fahad, A., Jin, Z., He, Z., Guo, Z., Xie, W., et al. (2024) · Journal of Materials Chemistry B · doi:10.1039/d4tb00288a · Cited by 8
Serotype-specific Binding Properties and Nanoparticle Characteristics Contribute to the Immunogenicity of rAAV1 Vectors
Ferrand, M., Rocha, S. D., Corre, G., Galy, A. H. M., & Boisgérault, F. (2015) · Molecular Therapy · doi:10.1038/mt.2015.59 · Cited by 8
A facile method to prepare non-cationic mRNA lipid-nanoparticles based on frame guided assembly strategy
Li, Y., Yuan, W., Tian, X., Zhu, C., Li, X., Chen, R., Hao, Z., Dong, Y., & Liu, D. (2023) · Nano Today · doi:10.1016/j.nantod.2023.101991 · Cited by 8
Buffering Capacity and Size of siRNA Polyplexes Influence Cytokine Levels
Leng, Q., Chou, S., Scaria, P. V., Woodle, M. C., & Mixson, A. J. (2012) · Molecular Therapy · doi:10.1038/mt.2012.206 · Cited by 8
This is the pre-peer-reviewed version of the following article:
Sm, C., Berger, S., Cannon, R. C., Ap, D., Djurfeldt, M., Eppler, J. M., Kriener, B., Furber, S. B., Graham, B. P., He, P., et al. (2012) · Cited by 8
Nanocarrier‐Mediated RNA Delivery Platform as a Frontier Strategy for Hepatic Disease Treatment: Challenges and Opportunities
Fan, J., Xiao, Z., Dong, Y., Ye, F., Yan, Q., Zhang, C., Yin, X., Li, Y., & Wang, T. (2024) · Advanced Healthcare Materials · doi:10.1002/adhm.202402933 · Cited by 7
A review on targeting tunable nanocarrier interaction, physiochemical properties, and futuristic nanocarrier
Pandey, S. S., Joshi, S., Tripathi, P., Gupta, A. R., & Yadav, J. S. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2025.167956 · Cited by 7
Immunogenic amines on lipid nanoparticles
Sharma, P., Breier, D., & Peer, D. (2024) · Nature Biomedical Engineering · doi:10.1038/s41551-024-01265-9 · Cited by 8
Self-citation
Sulforaphane Wrapped in Self-Assembled Nanomicelle Enhances the Effect of Sonodynamic Therapy on Glioma
Li, Y., Yang, X., Wei, Z., Niu, H., Wu, L., Chen, C., Liu, H., Cai, T., & Fan, H. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics17010034 · Cited by 7
“However, the liposome-induced cytotoxicity to normal cells is inevitable [47–49].”
Formulation and role of polymeric and inorganic nanoparticles in respiratory diseases
Chakraborty, A., & Selomulya, C. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-820658-4.00012-1 · Cited by 7
Biological toxicity of nanoparticles
Kakoty, V., Sarathlal, K. C., Pandey, M., Dubey, S. K., Kesharwani, P., & Taliyan, R. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820757-4.00016-8 · Cited by 7
Toxicity and biocompatibility of nanomaterials: In vivo studies
Darbasizadeh, B., Feyzi-barnaji, B., & Naderi, N. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-90792-7.00014-2 · Cited by 7
Design, optimization, characterization, and in vitro evaluation of metformin-loaded liposomes for triple negative breast cancer treatment
Vozgirdaite, D., Hervé-Aubert, K., Uzbekov, R. E., Chourpa, I., & Allard-Vannier, É. (2024) · Journal of Liposome Research · doi:10.1080/08982104.2024.2321528 · Cited by 7
“…HSPC is considered zwitterionic, possessing both negatively charged phosphate and carbonyl groups and positively charged choline groups, thus, implying that the particles should have neutral charge, this is not the increased toxicity to cells is higher for positively charged lipid vesicles [42].”
Elucidating allergic reaction mechanisms in response to SARS ‐ CoV ‐2 mRNA vaccination in adults
Shah, M. M., Layhadi, J. A., Hourcade, D. E., Fulton, W. T., Tan, T. J., Dunham, D., Chang, I., Vel, M. S., Fernandes, A. C., Lee, A., et al. (2024) · Allergy · doi:10.1111/all.16231 · Cited by 7
Enhanced Vascular Permeability in Solid Tumors: A Promise for Anticancer Nanomedicine
Taurin, S., & Greish, K. F. (2013) · Cancer metastasis · doi:10.1007/978-94-007-6028-8_4 · Cited by 7
Head group configuration increases the biocompatibility of cationic lipids for nucleic acid delivery
Gerile, G., Ganbold, T., Li, Y., & Baigude, H. (2017) · Journal of Materials Chemistry B · doi:10.1039/c7tb00317j · Cited by 7
A tissue chamber chip for assessing nanoparticle mobility in the extravascular space
Lusi, V., Moore, T. L., Laurino, F., Coclite, A., Perreira, R., Ferreira, M. F. M. M., Rizzuti, I. F., Palomba, R., Zunino, P., Duocastella, M., et al. (2019) · Biomedical Microdevices · doi:10.1007/s10544-019-0398-5 · Cited by 7
“With minor modifications, Multilamellar Vesicles (MLVs) were made by a mixture of PC, Chol and DPPE in a molar ratio of 60:20:20 (Peer and Margalit 2000; Peer and Margalit 2004; Peer et al. 2008; Kedmi et al. 2010).”
MethodSelf-citation
Modified mRNA-Based Vaccines Against Coronavirus Disease 2019
Wang, A. Y. L. (2022) · Cell Transplantation · doi:10.1177/09636897221090259 · Cited by 7
Lipidoids: A Combinatorial Approach to siRNA Delivery
Goldberg, M. S. (2012) · Advances in delivery science and technology · doi:10.1007/978-1-4614-4744-3_7 · Cited by 7
“Speci fi cally, excess charge is associated with nonspeci fi c interactions with biological surfaces, increased protein binding, opsonization, rapid clearance by the MPS, hemolysis, and cytotoxicity [ 28 ] .”
Background
Nanoscale Therapeutic System: Safety Assessment Features
Bovina, E., Романов, Б. К., Kazakov, A. S., Velts, N. Y., Журавлева, Е. О., Букатина, Т. М., Alyautdin, R. N., & Меркулов, В. А. (2019) · Safety and Risk of Pharmacotherapy · doi:10.30895/2312-7821-2019-7-3-127-138 · Cited by 7
“[47] были исследованы липидные наночастицы с положительным, отрицательным или нейтральным зарядом.”
In VivoEvaluation of Acute and Chronic Nanotoxicity
Nehoff, H. L., Parayath, N. N., Taurin, S., & Greish, K. F. (2014) · doi:10.1002/9781118856017.ch3 · Cited by 7
Chitosan siRNA Nanoparticles Produce Significant Non-Toxic Functional Gene Silencing in Kidney Cortices
Alameh, M., Naeini, A. T., Dwivedi, G., Lesage, F., Buschmann, M. D., & Lavertu, M. (2024) · Polymers · doi:10.3390/polym16172547 · Cited by 6

Authors: Kedmi, R., Ben-Arie, N., & Peer, D.
Affiliations: Tel Aviv University (IL)
Corresponding author: Peer, Dan
ORCID: Kedmi, Ranit
Peer, Dan
Venue: Biomaterials
Publisher: Elsevier BV
Published: 2010-09
Volume: 31
Issue: 26
Pages: 6867-6875
ISSN: 0142-9612 (ISSN-L)
DOI: 10.1016/j.biomaterials.2010.05.027
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks