{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T07:06:23Z","timestamp":1789369583732,"version":"build-2803163510"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100017170","name":"Thailand Science Research and Innovation","doi-asserted-by":"publisher","award":["197246"],"award-info":[{"award-number":["197246"]}],"id":[{"id":"10.13039\/501100017170","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Discover Nano"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Head and neck squamous cell carcinoma (HNSCC) remain one of the most aggressive malignancies worldwide, necessitating the development of targeted therapeutic strategies. While zinc oxide (ZnO) nanostructures have shown promise in nanomedicine, the mechanistic influence of nanoparticle morphology on HNSCC remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we synthesized and characterized green-synthesized spherical ZnO nanoparticles (NPs) and spiky ZnO nanoparticles (SNPs) using total polyphenols (TP) as a reducing and stabilizing agent. To track cellular interactions, the nanostructures were further modified with glioblastoma-derived eGFP tags. The antitumor efficacy and underlying mechanisms were evaluated across multiple HNSCC cell lines (Fadu, TU212, and TU686) using 2D cultures, 3D multicellular spheroids, and cellular internalization assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Chemical characterization revealed distinct architectural shifts between the spherical and spiky morphologies. Both nanoparticle types demonstrated significant dose-dependent anticancer activity; however, ZnO SNPs exhibited superior internalization and more pronounced tumor suppression in 3D spheroid models. Notably, ZnO SNPs showed higher efficacy in the highly aggressive hypopharyngeal cancer line (Fadu) compared to laryngeal carcinoma lines (TU212 and TU686).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Mechanistic investigations revealed that ZnO SNPs exert their antitumor effects by modulating reactive oxygen species (ROS) production, downregulating multidrug resistance-associated protein 1 (MRP1), and inhibiting glutathione peroxidase 4 (GPX4). This synergy triggers potent ROS-induced ferroptosis. Our findings suggest that the hierarchical morphology of ZnO SNPs enhances their therapeutic potential, offering a novel, targeted approach for the treatment of aggressive HNSCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s11671-026-04895-x","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T06:35:45Z","timestamp":1789367745000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["eGFP tagged ZnO nanoparticles from glioblastoma targeting ferroptosis and MRP1 in head and neck squamous cell carcinoma"],"prefix":"10.1186","volume":"21","author":[{"given":"Salida","family":"Ali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ontana","family":"Yotnarong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongle","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruochen","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruofan","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Na","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theeranan","family":"Tangthong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"4895_CR1","first-page":"2024","volume":"15","author":"J Yang","year":"2024","unstructured":"Yang J, Gu Z. Ferroptosis in head and neck squamous cell carcinoma: from pathogenesis to treatment. Front Pharmacology. 2024;15:2024.","journal-title":"Front Pharmacology"},{"key":"4895_CR2","first-page":"394","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clinicians. 2018;68:394\u2013424.","journal-title":"CA: A Cancer J Clinicians"},{"key":"4895_CR3","doi-asserted-by":"publisher","first-page":"5617","DOI":"10.1038\/onc.2015.32","volume":"34","author":"X Sun","year":"2015","unstructured":"Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene. 2015;34:5617\u201325.","journal-title":"Oncogene"},{"key":"4895_CR4","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.nano.2017.11.003","volume":"14","author":"PB Ezhuthupurakkal","year":"2018","unstructured":"Ezhuthupurakkal PB, Ariraman S, Arumugam S, Subramaniyan N, Muthuvel SK, Kumpati P, et al. Anticancer potential of ZnO nanoparticle-ferulic acid conjugate on Huh-7 and HepG2 cells and diethyl nitrosamine induced hepatocellular cancer on Wistar albino rat. Nanomedicine: Nanotechnology, Biol Med. 2018;14:415\u201328.","journal-title":"Nanomedicine: Nanotechnology, Biol Med"},{"key":"4895_CR5","doi-asserted-by":"publisher","first-page":"261","DOI":"10.14336\/AD.2020.0323","volume":"12","author":"J Ju","year":"2021","unstructured":"Ju J, Song Y-N, Wang K. Mechanism of ferroptosis: a potential target for cardiovascular diseases treatment. Aging Dis. 2021;12:261\u201376.","journal-title":"Aging Dis"},{"key":"4895_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-52217-x","volume":"14","author":"P Perumal","year":"2024","unstructured":"Perumal P, Sathakkathulla NA, Kumaran K, Ravikumar R, Selvaraj JJ, Nagendran V, et al. Green synthesis of zinc oxide nanoparticles using aqueous extract of shilajit and their anticancer activity against HeLa cells. Sci Rep. 2024;14:2204.","journal-title":"Sci Rep"},{"key":"4895_CR7","doi-asserted-by":"publisher","first-page":"30880","DOI":"10.1074\/jbc.R114.609248","volume":"289","author":"SP Cole","year":"2014","unstructured":"Cole SP. Multidrug resistance protein 1 (MRP1, ABCC1), a \u201cmultitasking\u201d ATP-binding cassette (ABC) transporter. J Biol Chem. 2014;289:30880\u20138.","journal-title":"J Biol Chem"},{"key":"4895_CR8","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1007\/s12274-009-9089-5","volume":"2","author":"S Ostrovsky","year":"2009","unstructured":"Ostrovsky S, Kazimirsky G, Gedanken A, Brodie C. Selective cytotoxic effect of ZnO nanoparticles on glioma cells. Nano Res. 2009;2:882\u201390.","journal-title":"Nano Res"},{"key":"4895_CR9","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-63258-7","volume":"14","author":"Y Mongy","year":"2024","unstructured":"Mongy Y, Shalaby T. Green synthesis of zinc oxide nanoparticles using Rhus coriaria extract and their anticancer activity against triple-negative breast cancer cells. Sci Rep. 2024;14:13470.","journal-title":"Sci Rep"},{"key":"4895_CR10","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-025-02670-z","volume":"42","author":"S Razzaq","year":"2025","unstructured":"Razzaq S, Fatima I, Moafian Z, Rahdar A, Fathi-Karkan S, Kharaba Z, et al. Nanomedicine innovations in colon and rectal cancer: advances in targeted drug and gene delivery systems. Med Oncol. 2025;42:113.","journal-title":"Med Oncol"},{"key":"4895_CR11","doi-asserted-by":"publisher","unstructured":"Seminars in Oncology 52 (6), 152429, 2025; Journal of King Saud University-Science 34, 102084, 2022; Inorganic Chemistry Communications 167, 112790, 2024; https:\/\/doi.org\/10.1007\/s12032-025-02670-z","DOI":"10.1007\/s12032-025-02670-z"},{"key":"4895_CR12","doi-asserted-by":"publisher","first-page":"2172","DOI":"10.1007\/s12011-020-02323-4","volume":"199","author":"MJ Khan","year":"2021","unstructured":"Khan MJ, Ahmad A, Khan MA, Siddiqui S. Zinc oxide nanoparticle induces apoptosis in human epidermoid carcinoma cells through reactive oxygen species and DNA degradation. Biol Trace Elem Res. 2021;199:2172\u201381.","journal-title":"Biol Trace Elem Res"},{"key":"4895_CR13","doi-asserted-by":"publisher","first-page":"9709","DOI":"10.1021\/acsomega.1c00310","volume":"6","author":"S Faisal","year":"2021","unstructured":"Faisal S, Jan H, Shah SA, Shah S, Khan A, Akbar MT, et al. Green synthesis of zinc oxide (ZnO) nanoparticles using aqueous fruit extracts of myristica fragrans: their characterizations and biological and environmental applications. ACS Omega. 2021;6:9709\u201322.","journal-title":"ACS Omega"},{"key":"4895_CR14","doi-asserted-by":"publisher","first-page":"112071","DOI":"10.1016\/j.msec.2021.112071","volume":"124","author":"Z Dang","year":"2021","unstructured":"Dang Z, Sun J, Fan J, Li J, Li X, Chen T. Zinc oxide spiky nanoparticles: a promising nanomaterial for killing tumor cells. Mater Sci Engineering: C. 2021;124:112071.","journal-title":"Mater Sci Engineering: C"},{"key":"4895_CR15","doi-asserted-by":"crossref","unstructured":"Farhan, M Insights on the role of polyphenols in combating cancer drug resistance. Biomedicines 2023, 11.","DOI":"10.3390\/biomedicines11061709"},{"key":"4895_CR16","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1007\/s00449-023-02886-1","volume":"46","author":"N Asif","year":"2023","unstructured":"Asif N, Amir M, Fatma T. Recent advances in the synthesis, characterization and biomedical applications of zinc oxide nanoparticles. Bioprocess Biosyst Eng. 2023;46:1377\u201398.","journal-title":"Bioprocess Biosyst Eng"},{"key":"4895_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-81384-0","volume":"14","author":"H Subramaniam","year":"2024","unstructured":"Subramaniam H, Lim CK, Tey LH, Wong LS, Djearamane S. Oxidative stress-induced cytotoxicity of HCC2998 colon carcinoma cells by ZnO nanoparticles synthesized from Calophyllum teysmannii. Sci Rep. 2024;14:30198.","journal-title":"Sci Rep"},{"key":"4895_CR18","doi-asserted-by":"publisher","first-page":"30532","DOI":"10.1021\/acsomega.3c03775","volume":"8","author":"A Wirwis","year":"2023","unstructured":"Wirwis A, Sadowski Z. Green synthesis of silver nanoparticles: optimizing green tea leaf extraction for enhanced physicochemical properties. ACS Omega. 2023;8:30532\u201349.","journal-title":"ACS Omega"},{"key":"4895_CR19","first-page":"660","volume":"4","author":"AC Dhanemozhi","year":"2017","unstructured":"Dhanemozhi AC, Rajeswari V, Sathyajothi S. Green synthesis of zinc oxide nanoparticle using green tea leaf extract for supercapacitor application. Mater Today: Proc. 2017;4:660\u20137.","journal-title":"Mater Today: Proc"},{"key":"4895_CR20","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/2807644","volume":"2022","author":"S Ibraheem","year":"2022","unstructured":"Ibraheem S, Kadhim AA, Kadhim KA, Kadhim IA, Jabir M. Zinc oxide nanoparticles as diagnostic tool for cancer cells. Int J Biomater. 2022;2022:2807644.","journal-title":"Int J Biomater"},{"key":"4895_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e31316","volume":"10","author":"H Maheswaran","year":"2024","unstructured":"Maheswaran H, Djearamane S, Tanislaus Antony Dhanapal AC, Wong LS. Cytotoxicity of green synthesized zinc oxide nanoparticles using musa acuminata on vero cells. Heliyon. 2024;10:e31316.","journal-title":"Heliyon"},{"key":"4895_CR22","doi-asserted-by":"publisher","first-page":"4234","DOI":"10.3390\/cancers16244234","volume":"16","author":"MT Yassin","year":"2024","unstructured":"Yassin MT, Al-Otibi FO, Al-Sahli SA, El-Wetidy MS, Mohamed S. Metal oxide nanoparticles as efficient nanocarriers for targeted cancer therapy: addressing chemotherapy-induced disabilities. Cancers. 2024;16:4234.","journal-title":"Cancers"},{"key":"4895_CR23","doi-asserted-by":"crossref","unstructured":"Deylam, M;Alizadeh, E;Sarikhani, M;Hejazy, M; Firouzamandi, M Zinc oxide nanoparticles promote the aging process in a size-dependent manner. Journal of Materials Science: Materials in Medicine 2021, 32.","DOI":"10.1007\/s10856-021-06602-x"},{"key":"4895_CR24","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1093\/toxsci\/kfw010","volume":"150","author":"R Pati","year":"2016","unstructured":"Pati R, Das I, Mehta RK, Sahu R, Sonawane A. Zinc-oxide nanoparticles exhibit genotoxic, clastogenic, cytotoxic and actin depolymerization effects by inducing oxidative stress responses in macrophages and adult mice. Toxicol Sci. 2016;150:454\u201372.","journal-title":"Toxicol Sci"},{"key":"4895_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-20830-3","volume":"12","author":"G Safwat","year":"2022","unstructured":"Safwat G, Soliman ESM, Mohamed HRH. Induction of ROS mediated genomic instability, apoptosis and G0\/G1 cell cycle arrest by erbium oxide nanoparticles in human hepatic Hep-G2 cancer cells. Sci Rep. 2022;12:16333.","journal-title":"Sci Rep"},{"key":"4895_CR26","doi-asserted-by":"publisher","unstructured":"Mashkoor, NR;Heydarnezhad, M;Aghabali, T;Barmi, FG;Sangani, H;Nikoujamal, N;et al. Ellagic acid-conjugated iron oxide nanoparticles inhibit the cell cycle in the G0\/G1 phase and induce extrinsic apoptosis in gastric cancer cell line. Chem Biodivers 2025, https:\/\/doi.org\/10.1002\/cbdv.202402294, e202402294.","DOI":"10.1002\/cbdv.202402294"},{"key":"4895_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2022.215854","volume":"546","author":"J Lee","year":"2022","unstructured":"Lee J, Roh J-L. Induction of ferroptosis in head and neck cancer: a novel bridgehead for fighting cancer resilience. Cancer Lett. 2022;546:215854.","journal-title":"Cancer Lett"},{"key":"4895_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-022-01212-0","volume":"8","author":"T Ma","year":"2022","unstructured":"Ma T, Du J, Zhang Y, Wang Y, Wang B, Zhang T. GPX4-independent ferroptosis\u2014a new strategy in disease\u2019s therapy. Cell Death Discovery. 2022;8:434.","journal-title":"Cell Death Discovery"},{"key":"4895_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-53837-7","volume":"15","author":"MT Herrera-Abreu","year":"2024","unstructured":"Herrera-Abreu MT, Guan J, Khalid U, Ning J, Costa MR, Chan J, et al. Inhibition of GPX4 enhances CDK4\/6 inhibitor and endocrine therapy activity in breast cancer. Nat Commun. 2024;15:9550.","journal-title":"Nat Commun"},{"key":"4895_CR30","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2021.100795","volume":"59","author":"KM Hanssen","year":"2021","unstructured":"Hanssen KM, Haber M, Fletcher JI. Targeting multidrug resistance-associated protein 1 (MRP1)-expressing cancers: beyond pharmacological inhibition. Drug Resist Updat. 2021;59:100795.","journal-title":"Drug Resist Updat"},{"key":"4895_CR31","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1016\/j.celrep.2019.01.043","volume":"26","author":"JY Cao","year":"2019","unstructured":"Cao JY, Poddar A, Magtanong L, Lumb JH, Mileur TR, Reid MA, et al. A genome-wide haploid genetic screen identifies regulators of glutathione abundance and ferroptosis sensitivity. Cell Rep. 2019;26:1544. e1548","journal-title":"Cell Rep"},{"key":"4895_CR32","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1007\/s11060-018-2835-3","volume":"138","author":"Y Li","year":"2018","unstructured":"Li Y, Liu Y, Ren J, Deng S, Yi G, Guo M, et al. miR-1268a regulates ABCC1 expression to mediate temozolomide resistance in glioblastoma. J Neuro-Oncology. 2018;138:499\u2013508.","journal-title":"J Neuro-Oncology"},{"key":"4895_CR33","doi-asserted-by":"publisher","first-page":"2931","DOI":"10.1016\/j.jmrt.2022.08.028","volume":"20","author":"V Selvanathan","year":"2022","unstructured":"Selvanathan V, Aminuzzaman M, Tan LX, Win YF, Guan Cheah ES, Heng MH, et al. Synthesis, characterization, and preliminary in vitro antibacterial evaluation of ZnO nanoparticles derived from soursop (Annona muricata L.) leaf extract as a green reducing agent. J Mater Res Technol. 2022;20:2931\u201341.","journal-title":"J Mater Res Technol"},{"key":"4895_CR34","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s13045-024-01564-3","volume":"17","author":"F Chen","year":"2024","unstructured":"Chen F, Kang R, Tang D, Liu J. Ferroptosis: principles and significance in health and disease. J Hematol Oncol. 2024;17:41 https:\/\/doi.org\/10.1186\/s13045-024-01564-3","journal-title":"J Hematol Oncol"},{"key":"4895_CR35","doi-asserted-by":"publisher","DOI":"10.1515\/gps-2024-0164","volume":"13","author":"Y Wong","year":"2024","unstructured":"Wong Y, Subramaniam H, Shing Wong L, Dhanapal A, Chan Y, Aminuzzaman M, et al. Green synthesis and characterization of CuO\/ZnO nanocomposite using Musa acuminata leaf extract for cytotoxic studies on colorectal cancer cells (HCC2998). Green Process Synth. 2024;13:20240164.","journal-title":"Green Process Synth"},{"key":"4895_CR36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ntm.2025.100097","volume":"4","author":"AM Mohammed","year":"2025","unstructured":"Mohammed AM, Mohammed M, Oleiwi JK, Ihmedee FH, Adam T, Betar BO, et al. The anticancer, antioxidant, and antimicrobial properties of ZnO nanoparticles: a comprehensive review. Nano TransMed. 2025;4:100097.","journal-title":"Nano TransMed"},{"key":"4895_CR37","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1226044","volume":"11","author":"HT Endale","year":"2023","unstructured":"Endale HT, Tesfaye W, Mengstie TA. ROS induced lipid peroxidation and their role in ferroptosis. Front Cell Developmental Biol. 2023;11:1226044.","journal-title":"Front Cell Developmental Biol"}],"container-title":["Discover Nano"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s11671-026-04895-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s11671-026-04895-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s11671-026-04895-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T06:35:49Z","timestamp":1789367749000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s11671-026-04895-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4895"],"URL":"https:\/\/doi.org\/10.1186\/s11671-026-04895-x","relation":{},"ISSN":["2731-9229"],"issn-type":[{"value":"2731-9229","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]},"assertion":[{"value":"27 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"438"}}