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Meta-analysis of cellular toxicity for cadmium-containing quantum dots
Abstract
Understanding the relationships between the physicochemical properties of engineered nanomaterials and their toxicity is critical for environmental and health risk analysis. However, this task is confounded by material diversity, heterogeneity of published data and limited sampling within individual studies. Here, we present an approach for analysing and extracting pertinent knowledge from published studies focusing on the cellular toxicity of cadmium-containing semiconductor quantum dots. From 307 publications, we obtain 1,741 cell viability-related data samples, each with 24 qualitative and quantitative attributes describing the material properties and experimental conditions. Using random forest regression models to analyse the data, we show that toxicity is closely correlated with quantum dot surface properties (including shell, ligand and surface modifications), diameter, assay type and exposure time. Our approach of integrating quantitative and categorical data provides a roadmap for interrogating the wide-ranging toxicity data in the literature and suggests that meta-analysis can help develop methods for predicting the toxicity of engineered nanomaterials.
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“Several literature studies have identified causal relationships between the biological outcomes and important ENMs properties.239”
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“Toxicity prediction models trained on these attribute combinations can sometimes identify causal relationships,239 which can be effectively achieved with the Bayesian Network (BN, also called a Bayesian Belief network, BBN) approach.249”
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Quantifying heterogeneity in a meta‐analysis
Higgins, J. P. T., & Thompson, S. G. (2002) · Statistics in Medicine · doi:10.1002/sim.1186 · Cited by 36,763
Sharifi, S., Behzadi, S., Laurent, S., Laird Forrest, M., Stroeve, P., & Mahmoudi, M. (2012) · Chem. Soc. Rev. · doi:10.1039/c1cs15188f · Cited by 1,460
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On the Cyto‐Toxicity Caused by Quantum Dots
Shiohara, A., Hoshino, A., Hanaki, K., Suzuki, K., & Yamamoto, K. (2004) · Microbiology and Immunology · doi:10.1111/j.1348-0421.2004.tb03478.x · Cited by 385
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Biological interactions of quantum dot nanoparticles in skin and in human epidermal keratinocytes
ZHANG, L., YU, W., COLVIN, V, & MONTEIRORIVIERE, N. (2008) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2007.12.022 · Cited by 247
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Bioluminescence-Based Energy Transfer Using Semiconductor Quantum Dots as Acceptors
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“A shell at the same time helps to reduce toxicity by preventing Cd2+ leaching, which remains a longstanding concern for their in vivo use [22].”
BackgroundSelf-citationTransition Metal Dichalcogenides for Biomedical Applications
Gong, L.-J., & Gu, Z.-J. (2019) · Two Dimensional Transition Metal Dichalcogenides · doi:10.1007/978-981-13-9045-6_8 · Cited by 16
Targeted nanodiamonds for identification of subcellular protein assemblies in mammalian cells
Lake, M., & Bouchard, L. (2017) · PLoS ONE · doi:10.1371/journal.pone.0179295 · Cited by 16
“They are also generally cytotoxic [39, 40] and are prone to intermittent fluorescence [41].”
BackgroundAdvantages and limitations of nanoparticle labeling for early diagnosis of infection
Laurentius, L. B., Owens, N. A., Park, J., Crawford, A. C., & Porter, M. D. (2016) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2016.1205489 · Cited by 17
Murase, N., Horie, M., Sawai, T., & Kawasaki, K. (2019) · Journal of nanoparticle research · doi:10.1007/s11051-018-4449-2 · Cited by 16
Red CdSe/ZnS QDs’ Intracellular Trafficking and Its Impact on Yeast Polarization and Actin Filament
Le, N., Routh, J. C., Kirk, C., Wu, Q., Patel, R., Keyes, C., & Kim, K. (2023) · Cells · doi:10.3390/cells12030484 · Cited by 13
Wang, X., He, K., Hu, Y., & Tang, M. X. (2022) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2022.110247 · Cited by 20
Designing the Surface Chemistry of Inorganic Nanocrystals for Cancer Imaging and Therapy
Delille, F., Pu, Y., Lequeux, N., & Pons, T. (2022) · Cancers · doi:10.3390/cancers14102456 · Cited by 22
“Typically less than 1 or 2% of the injected NP dose reaches and remains in the tumor [243,274].”
BackgroundCarvalho, I. C., Mansur, A., Carvalho, S., & Mansur, H. (2021) · Nanotheranostics · doi:10.7150/ntno.54491 · Cited by 15
“This bioassay was selected not only because it is the most widely accepted test for preliminary assessment of cytotoxicity of nanomaterials and medical devices [63] but also because it relies on the mitochondrial activity that will”
Ring-shaped corona proteins influence the toxicity of engineered nanoparticles to yeast
Ruotolo, R., Pira, G., Villani, M., Zappettini, A., & Marmiroli, N. (2018) · Environmental Science Nano · doi:10.1039/c7en01226h · Cited by 20
Nanosensors in Leukemia Management: Pioneering Real‐Time Biomarker Detection for Precision Oncology
Samarkhazan, H. S., Khaksari, M. N., Mirzazadeh, A., Siavashi, M., Pilehvari, N., & Mohammadi, M. H. (2025) · Nano Select · doi:10.1002/nano.70039 · Cited by 10
“For instance, certain quantum dots contain heavy metals like cadmium, raising toxicity issues upon degradation [39].”
Hydroporphyrin-Doped Near-Infrared-Emitting Polymer Dots for Cellular Fluorescence Imaging
Riahin, C., Meares, A. A., Esemoto, N. N., Ptaszek, M., LaScola, M. A., Pandala, N. G., Lavik, E., Yang, M., Stacey, G. S., Hu, D., et al. (2022) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.2c02551 · Cited by 16
Polymer dots and derived hybrid nanomaterials: A review
Kausar, A. (2021) · Journal of Plastic Film & Sheeting · doi:10.1177/87560879211010313 · Cited by 18
Status Quo in Data Availability and Predictive Models of Nano-Mixture Toxicity
Trinh, T. X., & Kim, J. (2021) · Nanomaterials · doi:10.3390/nano11010124 · Cited by 14
Aizik, G., Waiskopf, N., Agbaria, M., Ben-David-Naim, M., Nordling‐David, M. M., Jbara-Agbaria, D., Banin, U., & Golomb, G. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.12.009 · Cited by 17
Deciphering key nano-bio interface descriptors to predict nanoparticle-induced lung fibrosis
Cao, J., Yang, Y., Liu, X., Huang, Y., Xie, Q., Kadushkin, A. G., Nedelko, M. I., Wu, D., Aquilina, N. J., Li, X., et al. (2025) · Particle and Fibre Toxicology · doi:10.1186/s12989-024-00616-3 · Cited by 11
“For instance, considering that quantum dot (QD)-induced cell deaths are often attributed to surface chemistry factors such as size, ligand, and surface shell, Oh et al. successfully crafted predictive cytotoxicity models for cell viability and IC50 assessments [30].”
Predicting the cytotoxicity of nanomaterials through explainable, extreme gradient boosting
Conti, A., Campagnolo, L., Diciotti, S., Pietroiusti, A., & Toschi, N. (2022) · Nanotoxicology · doi:10.1080/17435390.2022.2156823 · Cited by 14
“…appear among the top ranking predictors, thus confirming previous studies pointing out these two characteristics as fundamental aspects associated with NP toxicity (Gatoo et al. 2014; Gernand and Casman 2014; Shin, Song, and Um 2015; Oh et al. 2016; Marvin et al. 2017; GarciaFernandez et al. 2020).”
BackgroundResultLong-term chemical biotransformation and pathways of Cd-based quantum dots in mice
Chen, G.-C., Zhang, Y.-J., Huang, D., Liu, Y., Li, C.-Y., & Wang, Q.-B. (2022) · Nano Today · doi:10.1016/j.nantod.2022.101504 · Cited by 13
2D nanomaterials in 3D/4D-printed biomedical devices
Das, M., Ambekar, R. S., Panda, S., Chakraborty, S., & Tiwary, C. (2021) · Journal of Materials Research · doi:10.1557/s43578-021-00287-2 · Cited by 13
Pagano, L., Caldara, M., Villani, M., Zappettini, A., Marmiroli, N., & Marmiroli, M. (2019) · Nanomaterials · doi:10.3390/nano9040512 · Cited by 13
“This point becomes fundamental, when also considering the QDs’ physico-chemical properties (size, surface charge, composition, stability, aggregation) related to the nano form compared to the bulk and ion forms, along with the possible scenarios of environmental and human exposure [5,19,54,55].”
BackgroundHong, W., Kuang, H., He, X., Yang, L., Yang, P., Chen, B., Aguilar, Z. P., & Xu, H. (2019) · Nanomaterials · doi:10.3390/nano9020257 · Cited by 17
“Moreover, there are several in vitro and in vivo studies aimed to explore the toxic effects and mechanisms of QDs [7,8].”
BackgroundWang, L., Xu, K., Hou, X., Han, Y., Liu, S., Wiraja, C., Yang, C., Yang, J., Wang, M., Dong, X., et al. (2017) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.7b01203 · Cited by 17
Therapeutic effect of quantum dots for cancer treatment
Zhao, M., Zhu, B., Yao, W.-J., & Chen, D.-F. (2016) · RSC Advances · doi:10.1039/c6ra24063a · Cited by 20
Roy, J., Pore, S., & Roy, K. (2023) · Beilstein Journal of Nanotechnology · doi:10.3762/bjnano.14.77 · Cited by 12
Saraiva, A. L., Vieira, T. N., Notário, A. F., Luiz, J., da Silva, C. D., Goulart, L., Dantas, N., Silva, A., & Espíndola, F. (2022) · Nanomedicine: Nanotechnology, Biology and Medicine · doi:10.1016/j.nano.2022.102539 · Cited by 12
Kumar, P., & Kumar, A. (2021) · Nanotoxicology · doi:10.1080/17435390.2021.2008039 · Cited by 12
“In the work reported by Oh et al. (2016), the best model developed by the RF method for epithelial cell viability exhibited a value of determination coefficient (R2E632) as 0.68 which is much lesser than the determination coefficients of the QFTR models developed in this work for hepatic cells.”
MethodInfluentialHorstmann, C., & Kim, K. (2021) · Genes · doi:10.3390/genes12030428 · Cited by 12
“Despite these attempts to improve their safety, concerns regarding exposure to QDs and QD-containing products persist [1,18].”
BackgroundRecent advances in nanoscale materials for antibody-based cancer theranostics
Kukkar, D., Kukkar, P., Kumar, V., Hong, J., Kim, K., & Deep, A. (2020) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2020.112787 · Cited by 17
Nanoinformatics: Artificial Intelligence and Nanotechnology in the New Decade.
Afantitis, A. (2020) · Combinatorial chemistry & high throughput screening · doi:10.2174/138620732301200316112000 · Cited by 12
New aspects of the environmental risks of quantum dots: prophage activation
Xu, J., He, H., Wang, Y., Yan, R., Zhou, L.-J., Liu, Y., Jiang, F., Maskow, T., & Liu, Y. (2018) · Environmental Science Nano · doi:10.1039/c8en00142a · Cited by 16
Chen, K., Li, K., Canchola, A., Liu, J., Liu, Q., & Chou, W. (2025) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2025.139353 · Cited by 11
Yu, X., Zheng, X., Yang, B., & Wang, J. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.06.164 · Cited by 10
Gram scale synthesis of QD450 core–shell quantum dots for cellular imaging and sorting
Vyshnava, S. S., Pandluru, G., Kanderi, D. K., Panjala, S. P., Banapuram, S., Paramasivam, K., Anupalli, R. R., Bontha, R. R., & Dowlathabad, M. R. (2020) · Applied Nanoscience · doi:10.1007/s13204-020-01261-w · Cited by 15
Ligand-conjugated quantum dots for fast sub-diffraction protein tracking in acute brain slices
Thal, L. B., Mann, V. R., Sprinzen, D., Mcbride, J., Reid, K. R., Tomlinson, I. A., McMahon, D. G., Cohen, B. E., & Rosenthal, S. (2019) · Biomaterials Science · doi:10.1039/c9bm01629e · Cited by 11
Mansur, A., Mansur, H., Carvalho, S., Lobato, Z. P., Leite, M. D. F., & Mansur, L. L. (2018) · ACS Omega · doi:10.1021/acsomega.8b02098 · Cited by 11
“18 − 20 Thus, in this study, we endeavor to design and synthesize for the fi rst time, novel ZnS QD nanoconjugates directly produced using PEA as the capping ligand and the functional biomolecule in a one-pot aqueous colloidal process.”
Part, F., Zaba, C., Bixner, O., Grünewald, T. A., Michor, H., Küpcü, S., Debreczeny, M., Francesco, E. D. V., Lassenberger, A., Schrittwieser, S., et al. (2018) · Chemistry of Materials · doi:10.1021/acs.chemmater.8b00431 · Cited by 14
Oh, E., Delehanty, J., Klug, C., Susumu, K., Algar, W. R., Goswami, R., & Medintz, I. L. (2018) · Chemical Communications · doi:10.1039/c7cc08650d · Cited by 11
Self-citationFontana, J., Yin, H.-J., Chen, Y., Florez, R., Brismar, H., & Fu, Y. (2017) · International Journal of Nanomedicine · doi:10.2147/ijn.s145608 · Cited by 11
Applications of Quantum Dots in Biosensors and Diagnostics
Altintaş, Z., Davis, F., & Scheller, F. (2017) · doi:10.1002/9781119065036.ch9 · Cited by 11
Hooe, S. L., Breger, J. C., & Medintz, I. L. (2024) · Molecular Systems Design & Engineering · doi:10.1039/d4me00017j · Cited by 21
Self-citationDeng, P., Zhou, Q.-X., Luo, J.-W., Hu, X.-G., & Yu, F.-B. (2023) · Science of the Total Environment · doi:10.1016/j.scitotenv.2023.169191 · Cited by 10
Alwraikat, A., Jaradat, A., Marji, S. M., Bayan, M. F., Alomari, E., Naser, A., & Alyami, M. H. (2023) · Italian National Conference on Sensors · doi:10.3390/s23208453 · Cited by 10
“…to the fact that most these systems rely on silica nanoparticles that might induce immunotoxicity [24], polyacrylamide nanoparticles that are composed of repeating monomers which could increase the cellular apoptosis/cytotoxicity [25], or quantum dots that could lead to cellular toxicity [26].”
BackgroundQuantum dots-labeled polymeric scaffolds for in vivo tracking of degradation and tissue formation
Sim, K. H., Mir, M., Jelke, S., Tarafder, S., Kim, J.-H., & Lee, C. H. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.03.003 · Cited by 10
“It has been suggested that QD cytotoxicity is associated with the physiochemical properties, as connected with some inherent chemical feature such as the elements contained in the QD core [31,33].”
BackgroundBai, C.-C., Wei, T., Zou, L.-Y., Liu, N., Huang, X.-Q., & Tang, M. (2022) · Journal of Applied Toxicology · doi:10.1002/jat.4291 · Cited by 10
“specific surface effect, and macroscopic quantum tunneling effect (Moulick et al., 2017; Oh et al., 2016).”
BackgroundGallo, V., Zappettini, A., Villani, M., Marmiroli, N., & Marmiroli, M. (2021) · Nanomaterials · doi:10.3390/nano11030615 · Cited by 14
“Generally, the influence of exposure duration on Cd-based QDs toxicity is insufficiently understood [19,20].”
BackgroundAsgher, M., Qamar, S. A., Sadaf, M., & Iqbal, H. M. N. (2020) · Biomedical Physics & Engineering Express · doi:10.1088/2057-1976/ab6e1d · Cited by 12
Buchtelova, H., Strmiska, V., Skubalova, Z., Dostalova, S., Michalek, P., Křížková, S., Hynek, D., Kalina, L., Richtera, L., Moulick, A., et al. (2018) · Journal of Nanobiotechnology · doi:10.1186/s12951-018-0369-7 · Cited by 10
“On the other hand, un-doped CdTe QDs were toxic to the cells, which is in good agreement with previously published studies [7, 11, 26, 27].”
ResultNcapayi, V., Parani, S., Songca, S. P., Kodama, T., & Oluwafemi, O. S. (2017) · Materials Letters · doi:10.1016/j.matlet.2017.08.042 · Cited by 10
Metadata
- Authors
- Oh, E., Liu, R., Nel, A., Gemill, K. B., Bilal, M., Cohen, Y., & Medintz, I. L.
- Affiliations
- United States Naval Research Laboratory (US)
- University of California, Los Angeles (US)
- Corresponding author
- Liu, Rong
- Cohen, Yoram
- Medintz, Igor L.
- Venue
- Nature Nanotechnology
- Published
- 2016-02-29
- Volume
- 11
- Issue
- 5
- Pages
- 479-486
- ISSN
- 1748-3387 (ISSN-L)
- 1748-3395
- OpenAlex
- W2292437912
- Cited by
- 502
- References
- 0
- Citations by year
- 2026: 24 · 2025: 36 · 2024: 39 · 2023: 40 · 2022: 62 · 2021: 53 · 2020: 78 · 2019: 44 · 2018: 56 · 2017: 48 · 2016: 22
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Nanotechnology (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation
- Defense Threat Reduction Agency
- U.S. Naval Research Laboratory
- Topics
- Physical Sciences › Materials Science › Materials Chemistry › Quantum Dots Synthesis And Properties
- Physical Sciences › Materials Science › Materials Chemistry › Nanoparticles: synthesis and applications
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
- Keywords
- cadmium quantum dots, semiconductor quantum dots, cytotoxicity, engineered nanomaterials, nanoparticle toxicity, cell viability, surface modification, ligands, shells, particle diameter, toxicity prediction, physicochemical properties, random forest regression
- MeSH terms
- Animals, Cadmium, Cell Survival, Humans, Models, Theoretical, Inhibitory Concentration 50, Quantum Dots, Workflow
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