Copper-Based Nanoparticles in Cancer Therapy: Integrating Synthesis, Biological Interactions, Mechanistic Insights

Abstract

Copper-based nanoparticles (CuNPs) have emerged as a versatile and cost-effective platform in cancer nanomedicine, driven by their intrinsic redox activity and tunable physicochemical properties. Their anticancer activity largely involves amplification of reactive oxygen species (ROS), which impair mitochondrial functions, damages DNA, delays cell division and induces programmed cell death. Interestingly, the cause of selective cytotoxicity of CuNPs over normal tissues is the high basal oxidative stress in cancerous cells. The stability, selectivity, and functional performance of CuNPs have been enhanced lately by the new synthesis methods, surface engineering and the hybrid nanostructures. In preclinical investigations, dose-dependent anti-cancer activity has been demonstrated in a wide range of tumor models and biosafety issues suggest the significance of dose control of oxidative stress and the unwarranted consequences. In comparison to other metal nanoparticles such as silver and gold, CuNPs can provide a favorable balance among therapeutic activity, scalability, and cost-effectiveness. Regardless of these benefits, there are oxidative instability, reproducibility, and limited clinical translation. The development of the future will rely on using CuNPs in combination regimens and customized nanomedicine, and rigorous in vivo validation and clinical evaluation. Altogether, CuNPs are a potentially powerful but immature nanotherapeutic platform that has a high chance of being used to treat cancer in the next generation.

Keywords:

Copper nanoparticles, Cancer therapy, Oxidative stress, Apoptosis, Nanomedicine

References

Elbarazi I, Ahmed LA. Alleviating the Global Burden of Cancer Through Prevention and Early Detection. Cancer Control 2025;32:10732748251378666. https://doi.org/10.1177/10732748251378666.

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209–49. https://doi.org/10.3322/caac.21660.

Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology 2007 2:12 2007;2:751–60. https://doi.org/10.1038/nnano.2007.387.

Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol 2018;15:81–94. https://doi.org/10.1038/nrclinonc.2017.166.

Chehelgerdi M, Chehelgerdi M, Allela OQB, Pecho RDC, Jayasankar N, Rao DP, et al. Progressing nanotechnology to improve targeted cancer treatment: overcoming hurdles in its clinical implementation. Mol Cancer 2023;22:169. https://doi.org/10.1186/S12943-023-01865-0.

Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nature Reviews Cancer 2016 17:1 2016;17:20–37. https://doi.org/10.1038/nrc.2016.108.

Patra JK, Das G, Fraceto LF, Campos EVR, Rodriguez-Torres MDP, Acosta-Torres LS, et al. Nano based drug delivery systems: recent developments and future prospects. Journal of Nanobiotechnology 2018 16:1 2018;16:71-. https://doi.org/10.1186/s12951-018-0392-8.

Khan I, Saeed K, Khan I. Nanoparticles: Properties, applications and toxicities. Arabian Journal of Chemistry 2019;12:908–31. https://doi.org/10.1016/j.arabjc.2017.05.011.

Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. Journal of Controlled Release 2000;65:271–84. https://doi.org/10.1016/S0168-3659(99)00248-5.

Conde J, Doria G, Baptista P. Noble Metal Nanoparticles Applications in Cancer. J Drug Deliv 2012;2012:751075. https://doi.org/10.1155/2012/751075.

Galarza-Arévalo GE, Gonzلlez MP, Romero MP. Clinical Applications and Future Prospects of Metallic Nanoparticles in Diagnosis and Therapy. Int J Nanomedicine 2026;21:567931. https://doi.org/10.2147/IJN.S567931.

Xia C, Luo Z, Feng Z, Zhang Q, Xia C. Mechanism and application of copper-based nanomedicines in activating tumor immunity through oxidative stress modulation. Front Pharmacol 2025;16:1646890. https://doi.org/10.3389/FPHAR.2025.1646890.

Pellosi DS, Paiva GSM, Vital VG, Mendes AL, Santos NG, Kuriki FK, et al. Harnessing Copper Nanoparticles for Antimicrobial Applications: Advances and Challenges. Antibiotics 2025, Vol 14, Page 1170 2025;14:1170. https://doi.org/10.3390/ANTIBIOTICS14111170.

Vyas RH, Ranch D, Vyas B, Naik Z, Kapoor DU. Emerging role of copper nanoparticles in the diagnosis and treatment of lung cancer. Journal of Trace Elements and Minerals 2026;16:100295. https://doi.org/10.1016/J.JTEMIN.2026.100295.

Aishajiang R, Liu Z, Wang T, Zhou L, Yu D. Recent Advances in Cancer Therapeutic Copper-Based Nanomaterials for Antitumor Therapy. Molecules 2023, Vol 28, Page 2303 2023;28:2303. https://doi.org/10.3390/MOLECULES28052303.

Woźniak-Budych MJ, Staszak K, Staszak M. Copper and Copper-Based Nanoparticles in Medicine—Perspectives and Challenges. Molecules 2023;28:6687. https://doi.org/10.3390/molecules28186687.

Yang YY, Zhang XR, Fu MQ, Li R, Chen B, Li X, et al. Engineering copper-based nanoplatforms in cancer therapy. Mater Des 2026;267:116337. https://doi.org/10.1016/J.MATDES.2026.116337.

Lakkakula J, Kumar A, Singh N, Singh A, Uddin I. Unveiling the therapeutic potential of copper nanoparticles for cancer treatment: a systematic review. Int Immunopharmacol 2026;178:116519. https://doi.org/10.1016/J.INTIMP.2026.116519.

Song Y, Tan KB, Zhou SF, Zhan G. Biocompatible Copper-Based Nanocomposites for Combined Cancer Therapy. ACS Biomater Sci Eng 2024;10:3673–92. https://doi.org/10.1021/ACSBIOMATERIALS.4C00586.

Naikoo G, Al-Mashali F, Arshad F, AL-Maashani N, Hassan IU, AL Baraami Z, et al. An Overview of Copper Nanoparticles: Synthesis, Characterisation and Anticancer Activity. Curr Pharm Des 2021;27:4416–32. https://doi.org/10.2174/1381612827666210804100303.

Antonio-Pérez A, Durلn-Armenta LF, Pérez-Loredo MG, Torres-Huerta AL. Biosynthesis of Copper Nanoparticles with Medicinal Plants Extracts: From Extraction Methods to Applications. Micromachines (Basel) 2023;14:1882. https://doi.org/10.3390/MI14101882.

Lu R, Hao W, Kong L, Zhao K, Bai H, Liu Z. A simple method for the synthesis of copper nanoparticles from metastable intermediates. RSC Adv 2023;13:14361. https://doi.org/10.1039/D3RA01082A.

Javed R, Zia M, Naz S, Aisida SO, Ain N ul, Ao Q. Role of capping agents in the application of nanoparticles in biomedicine and environmental remediation: recent trends and future prospects. J Nanobiotechnology 2020;18:1–15. https://doi.org/10.1186/s12951-020-00704-4.

Farooq S, Habib M, Cardozo O, Ullah K, Pandey AK, Said Z. Exploring the impact of particle stability, size, and morphology on nanofluid thermal conductivity: A comprehensive review for energy applications. Adv Colloid Interface Sci 2025;341:103495. https://doi.org/10.1016/J.CIS.2025.103495.

Thanh NTK, Maclean N, Mahiddine S. Mechanisms of Nucleation and Growth of Nanoparticles in Solution. Chem Rev 2014;114:7610–30. https://doi.org/10.1021/cr400544s.

Pourmadadi M, Holghoomi R, shamsabadipour A, Maleki-baladi R, Rahdar A, Pandey S. Copper nanoparticles from chemical, physical, and green synthesis to medicinal application: A review. Plant Nano Biology 2024;8:100070. https://doi.org/10.1016/j.plana.2024.100070.

Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nature Biotechnology 2015 33:9 2015;33:941–51. https://doi.org/10.1038/nbt.3330.

Vodyashkin A, Stoinova A, Kezimana P. Promising biomedical systems based on copper nanoparticles: Synthesis, characterization, and applications. Colloids Surf B Biointerfaces 2024;237:113861. https://doi.org/10.1016/j.colsurfb.2024.113861.

Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R. Engineering precision nanoparticles for drug delivery. Nature Reviews Drug Discovery 2020 20:2 2020;20:101–24. https://doi.org/10.1038/s41573-020-0090-8.

Pricop A, Negrea A, Pascu B, Nemeş NS, Ciopec M, Negrea P, et al. Copper Nanoparticles Synthesized by Chemical Reduction with Medical Applications. International Journal of Molecular Sciences 2025, Vol 26, Page 1628 2025;26:1628. https://doi.org/10.3390/IJMS26041628.

Molahalli V, Sharma A, Bijapur K, Soman G, Shetty A, Sirichandana B, et al. Properties, Synthesis, and Characterization of Cu-Based Nanomaterials. ACS Symposium Series 2024;1466:1–33. https://doi.org/10.1021/BK-2024-1466.CH001.

Luque-Jacobo CM, Cespedes-Loayza AL, Echegaray-Ugarte TS, Cruz-Loayza JL, Cruz I, de Carvalho JC, et al. Biogenic Synthesis of Copper Nanoparticles: A Systematic Review of Their Features and Main Applications. Molecules 2023;28:4838. https://doi.org/10.3390/molecules28124838.

Powar NS, Patel VJ, Pagare PK, Pandav RS. Chemical Methodologies Cu Nanoparticle: Synthesis, Characterization and Application Graphical Abstract. Chemical Methodologies 2019;3:457–80. https://doi.org/10.22034/chemm.2019.154075.1112.

Amaliyah S, Pangesti DP, Masruri M, Sabarudin A, Sumitro SB. Green synthesis and characterization of copper nanoparticles using Piper retrofractum Vahl extract as bioreductor and capping agent. Heliyon 2020;6:e04636. https://doi.org/10.1016/j.heliyon.2020.e04636.

Lungu II, Stefanache A, Anton N, Lungu A, Platon V-M, Mitran A-M, et al. Green-Synthesized Copper and Copper Oxide Nanoparticles: Structural Characterization and Evaluation of Biological Activity. Antioxidants 2026, Vol 15, 2026;15:339. https://doi.org/10.3390/antiox15030339.

Banger A, Kumari A, Jangid NK, Jadoun S, Srivastava A, Srivastava M. A review on green synthesis and characterisation of copper nanoparticles using plant extracts for biological applications. Environmental Technology Reviews 2025;14:94–126. https://doi.org/10.1080/21622515.2025.2453950.

Mittal AK, Chisti Y, Banerjee UC. Synthesis of metallic nanoparticles using plant extracts. Biotechnol Adv 2013;31:346–56. https://doi.org/10.1016/j.biotechadv.2013.01.003.

Iravani S. Green synthesis of metal nanoparticles using plants. Green Chemistry 2011;13:2638–50. https://doi.org/10.1039/c1gc15386b.

[39] Jadoun S, Arif R, Jangid NK, Meena RK. Green synthesis of nanoparticles using plant extracts: a review. Environmental Chemistry Letters 2020 19:1 2020;19:355–74. https://doi.org/10.1007/s10311-020-01074-x.

Ahmed S, Ahmad M, Swami BL, Ikram S. A review on plants extract mediated synthesis of silver nanoparticles for antimicrobial applications: A green expertise. J Adv Res 2016;7:17–28. https://doi.org/10.1016/j.jare.2015.02.007.

Wei Q, Pan Y, Zhang Z, Yan S, Li Z. Copper-based nanomaterials for biomedical applications. Chemical Engineering Journal 2024;483:149040. https://doi.org/10.1016/j.cej.2024.149040.

Khosravi N, Alzufairi A, Zahed P, Abouchenari A, Asgaran S, Reza-Soltani S, et al. Biomedical applications of copper nanoparticles: an up-to-date overview. Journal of Composites and Compounds 2024;6. https://doi.org/10.61186/JCC.6.4.1.

Nagar N, Devra V. Green synthesis and characterization of copper nanoparticles using Azadirachta indica leaves. Mater Chem Phys 2018;213:44–51. https://doi.org/10.1016/j.matchemphys.2018.04.007.

Naveen P, Gopi.Mamidi Dr. Synergistic Phytogenic Synthesis of Copper Nanoparticles Using Camellia sinensis and Ocimum sanctum: Structural, Potent Antibacterial, and Mechanistic Insights. World Journal of Environmental Engineering, Vol 10, 2025, Pages 1-6 2025;10:1–6. https://doi.org/10.12691/wjee-10-1-1.

Ramkumar R, Sapru S, Archana PP. Synthesis and Catalytic Applications of Ultrasmall Copper Nanoparticles Using Aloe Vera Plant Extract 2020. https://doi.org/10.26434/chemrxiv.13187780.v1.

Alsamhary KE. Moringa oleifera seed based green synthesis of copper nanoparticles: Characterization, environmental remediation and antimicrobial activity. Saudi J Biol Sci 2023;30:103820. https://doi.org/10.1016/j.sjbs.2023.103820.

Kaur P, Thakur R, Chaudhury A. Biogenesis of copper nanoparticles using peel extract of Punica granatum and their antimicrobial activity against opportunistic pathogens. Green Chem Lett Rev 2016;9:33–8. https://doi.org/10.1080/17518253.2016.1141238.

Li J, Cai T, Wu G. Effect of Cu Nanoparticles Green-Formulated Using Allium sativum Extract Against Pseudomonas aeruginosa in Mice Lung Infection Model. Biol Trace Elem Res 2025. https://doi.org/10.1007/s12011-025-04851-3.

Gahlawat G, Choudhury AR. A review on the biosynthesis of metal and metal salt nanoparticles by microbes. RSC Adv 2019;9:12944–67. https://doi.org/10.1039/c8ra10483b.

Saravanan A, Kumar PS, Karishma S, Vo DVN, Jeevanantham S, Yaashikaa PR, et al. A review on biosynthesis of metal nanoparticles and its environmental applications. Chemosphere 2021;264:128580. https://doi.org/10.1016/j.chemosphere.2020.128580.

View of Synthesis and Biological Activities of Cu-Nanoparticles from Aspergillus niger n.d. https://journalajbge.com/index.php/AJBGE/article/view/91/181 (accessed March 13, 2026).

Chand Mali S, Dhaka A, Sharma S, Trivedi R. Review on biogenic synthesis of copper nanoparticles and its potential applications. Inorg Chem Commun 2023;149:110448. https://doi.org/10.1016/j.inoche.2023.110448.

Mohamed SH, Othman BA, Abd-Elhalim BT, Seada MNA. Copper nanoparticles biosynthesis by Priestia megaterium and its application as antibacterial and antitumor agents. Scientific Reports 2024 14:1 2024;14:23615-. https://doi.org/10.1038/s41598-024-72598-3.

Tito IA, Uddin S, Islam S, Bhowmik S. Copper Nanoparticle(CuNP’s)Synthesis: A review of the various ways with Photocatalytic and Antibacterial Activity. Oriental Journal Of Chemistry 2021;37:1030–40. https://doi.org/10.13005/OJC/370503.

Jeevanandam J, Barhoum A, Chan YS, Dufresne A, Danquah MK. Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations. Beilstein Journal of Nanotechnology 9:98 2018;9:1050–74. https://doi.org/10.3762/bjnano.9.98.

Nasrollahzadeh M, Sajadi SM, Sajjadi M, Issaabadi Z. An Introduction to Nanotechnology. Interface Science and Technology 2019;28:1–27. https://doi.org/10.1016/B978-0-12-813586-0.00001-8.

Bhati M. Biogenic synthesis of metallic nanoparticles: Principles and applications. Mater Today Proc 2023;81:882–7. https://doi.org/10.1016/j.matpr.2021.04.272.

[58] Parveen K, Banse V, Ledwani L. Green synthesis of nanoparticles: Their advantages and disadvantages. AIP Conf Proc 2016;1724. https://doi.org/10.1063/1.4945168.

Ren G, Hu D, Cheng EWC, Vargas-Reus MA, Reip P, Allaker RP. Characterisation of copper oxide nanoparticles for antimicrobial applications. Int J Antimicrob Agents 2009;33:587–90. https://doi.org/10.1016/j.ijantimicag.2008.12.004.

Ma X, Zhou S, Xu X, Du Q. Copper-containing nanoparticles: Mechanism of antimicrobial effect and application in dentistry-a narrative review. Front Surg 2022;9:905892. https://doi.org/10.3389/fsurg.2022.905892.

Al-Hakkani MF. Biogenic copper nanoparticles and their applications: A review. SN Appl Sci 2020;2. https://doi.org/10.1007/s42452-020-2279-1.

Makarov V V., Love AJ, Sinitsyna O V., Makarova SS, Yaminsky I V., Taliansky ME, et al. “Green” nanotechnologies: Synthesis of metal nanoparticles using plants. Acta Naturae 2014;6:35–44. https://doi.org/10.32607/20758251-2014-6-1-35-44.

Nasrollahzadeh M, Sajjadi M, Sajadi SM, Issaabadi Z. Green Nanotechnology. Interface Science and Technology 2019;28:145–98. https://doi.org/10.1016/B978-0-12-813586-0.00005-5.

Yimeng S, Huilun X, Ziming L, Kejun L, Chaima M, Xiangyu Z, et al. Copper-Based Nanoparticles as Antibacterial Agents. Eur J Inorg Chem 2023;26:e202200614. https://doi.org/10.1002/ejic.202200614.

Sielska A, Skuza L. Copper Nanoparticles in Aquatic Environment: Release Routes and Oxidative Stress-Mediated Mechanisms of Toxicity to Fish in Various Life Stages and Future Risks. Current Issues in Molecular Biology 2025, Vol 47, Page 472 2025;47:472. https://doi.org/10.3390/CIMB47060472.

Hall J, Mekapothula S, Coxhill R, Craske D, Varney AM, Cave GWV, et al. Surface-Functionalised Copper Oxide Nanoparticles: A Pathway to Multidrug-Resistant Pathogen Control in Medical Devices. Nanomaterials 2024;14:1899. https://doi.org/10.3390/NANO14231899/S1.

Chitra SR, Rohini V, Nagarajan D, Bhamuni MR, Asha G, Joshaline CM. A Review Of The Effects Of Nanoparticles’ Physicochemical Properties On Reactions In Biological Systems As Drug Delivery Systems. International Journal of Drug Delivery Technology 2026;16. https://doi.org/10.25258/IJDDT.16.18S.7.

Albanese A, Tang PS, Chan WCW. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng 2012;14:1–16. https://doi.org/10.1146/ANNUREV-BIOENG-071811-150124.

Li L, Fernلndez-Cruz ML, Connolly M, Schuster M, Navas JM. Dissolution and aggregation of Cu nanoparticles in culture media: effects of incubation temperature and particles size. Journal of Nanoparticle Research 2015;17. https://doi.org/10.1007/s11051-015-2865-0.

Murugesan S, Balasubramanian S, Perumal E. Copper oxide nanoparticles induced reactive oxygen species generation: A systematic review and meta-analysis. Chem Biol Interact 2025;405:111311. https://doi.org/10.1016/j.cbi.2024.111311.

Jhuang LS, Kumar G, Chen FC. Localized surface plasmon resonance of copper nanoparticles improves the performance of quasi-two-dimensional perovskite light-emitting diodes. Dyes and Pigments 2021;188:109204. https://doi.org/10.1016/j.dyepig.2021.109204.

Ojha NK, Zyryanov G V., Majee A, Charushin VN, Chupakhin ON, Santra S. Copper nanoparticles as inexpensive and efficient catalyst: A valuable contribution in organic synthesis. Coord Chem Rev 2017;353:1–57. https://doi.org/10.1016/j.ccr.2017.10.004.

Recent progress in copper nanomaterials: catalysis, energy, biomedicine, and environmental applications - Materials Advances (RSC Publishing) DOI:10.1039/D5MA00484E n.d. https://pubs.rsc.org/en/content/articlehtml/2025/ma/d5ma00484e (accessed March 18, 2026).

Soloviev M, editor. Nanoparticles in Biology and Medicine 2012;906. https://doi.org/10.1007/978-1-61779-953-2.

Cedervall T, Lynch I, Lindman S, Berggهrd T, Thulin E, Nilsson H, et al. Understanding the nanoparticle-protein corona using methods to quntify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci U S A 2007;104:2050–5. https://doi.org/10.1073/pnas.0608582104.

Pozzi D, Caracciolo G, Digiacomo L, Colapicchioni V, Palchetti S, Capriotti AL, et al. The biomolecular corona of nanoparticles in circulating biological media. Nanoscale 2015;7:13958–66. https://doi.org/10.1039/c5nr03701h.

Sahay G, Alakhova DY, Kabanov A V. Endocytosis of nanomedicines. Journal of Controlled Release 2010;145:182–95. https://doi.org/10.1016/j.jconrel.2010.01.036.

Gustafson HH, Holt-Casper D, Grainger DW, Ghandehari H. Nanoparticle uptake: The phagocyte problem. Nano Today 2015;10:487–510. https://doi.org/10.1016/j.nantod.2015.06.006.

Zhu M, Nie G, Meng H, Xia T, Nel A, Zhao Y. Physicochemical properties determine nanomaterial cellular uptake, transport and fate. Acc Chem Res 2012;46:622. https://doi.org/10.1021/ar300031y.

Liu J, Liu Z, Pang Y, Zhou H. The interaction between nanoparticles and immune system: application in the treatment of inflammatory diseases. J Nanobiotechnology 2022;20:127. https://doi.org/10.1186/s12951-022-01343-7.

Kou L, Sun J, Zhai Y, He Z. The endocytosis and intracellular fate of nanomedicines: Implication for rational design. Asian J Pharm Sci 2013;8:1–10. https://doi.org/10.1016/j.ajps.2013.07.001.

Simon-Deckers A, Gouget B, Mayne-L’Hermite M, Herlin-Boime N, Reynaud C, Carrière M. In vitro investigation of oxide nanoparticle and carbon nanotube toxicity and intracellular accumulation in A549 human pneumocytes. Toxicology 2008;253:137–46. https://doi.org/10.1016/j.tox.2008.09.007.

Banerjee A, Qi J, Gogoi R, Wong J, Mitragotri S. Role of Nanoparticle Size, Shape and Surface Chemistry in Oral Drug Delivery. J Control Release 2016;238:176. https://doi.org/10.1016/j.jconrel.2016.07.051.

Adjei IM, Sharma B, Labhasetwar V. Nanoparticles: Cellular uptake and cytotoxicity. Adv Exp Med Biol 2014;811:74–91. https://doi.org/10.1007/978-94-017-8739-0_5.

Hwang J, Kang J, Oh N, Li C, Yoo CY, Kwak M. Effect of Surface Charge of Nanoparticles on Cellular Uptake in HeLa Cells. Langmuir 2025;41:13192–8. https://doi.org/10.1021/acs.langmuir.5c00832.

Jo DH, Kim JH, Lee TG, Kim JH. Size, surface charge, and shape determine therapeutic effects of nanoparticles on brain and retinal diseases. Nanomedicine 2015;11:1603–11. https://doi.org/10.1016/j.nano.2015.04.015.

Behzadi S, Serpooshan V, Tao W, Hamaly MA, Alkawareek MY, Dreaden EC, et al. Cellular Uptake of Nanoparticles: Journey Inside the Cell. Chem Soc Rev 2017;46:4218. https://doi.org/10.1039/c6cs00636a.

Leroueil PR, Hong S, Mecke A, Baker JR, Orr BG, Holl MMB. Nanoparticle Interaction with Biological Membranes: Does Nanotechnology present a Janus Face? Acc Chem Res 2007;40:335. https://doi.org/10.1021/AR600012Y.

Fahmy B, Cormier SA. Copper oxide nanoparticles induce oxidative stress and cytotoxicity in airway epithelial cells. Toxicology in Vitro 2009;23:1365–71. https://doi.org/10.1016/j.tiv.2009.08.005.

Chevallet M, Veronesi G, Fuchs A, Mintz E, Michaud-Soret I, Deniaud A. Impact of labile metal nanoparticles on cellular homeostasis. Current developments in imaging, synthesis and applications. Biochimica et Biophysica Acta (BBA) - General Subjects 2017;1861:1566–77. https://doi.org/10.1016/J.BBAGEN.2016.12.012.

Neogi N, Choudhury KP, Hossain I, Hossain S, Sazid MdG. Nanoparticle-Induced Oxidative Stress: Mechanisms and Implications for Human Health and Environmental Safety. Environmental and Earth Sciences Proceedings 2025, Vol 37, 2025;37:1. https://doi.org/10.3390/eesp2025037001.

Han JW, Gurunathan S, Jeong JK, Choi YJ, Kwon DN, Park JK, et al. Oxidative stress mediated cytotoxicity of biologically synthesized silver nanoparticles in human lung epithelial adenocarcinoma cell line. Nanoscale Res Lett 2014;9. https://doi.org/10.1186/1556-276X-9-459.

Shadmani P, Mehrafrooz B, Montazeri A, Naghdabadi R. Protein corona impact on nanoparticle-cell interactions: toward an energy-based model of endocytosis. J Phys Condens Matter 2020;32. https://doi.org/10.1088/1361-648X/ab5a14.

Sun Y, Zhou Y, Rehman M, Wang YF, Guo S. Protein Corona of Nanoparticles: Isolation and Analysis. Chem and Bio Engineering 2024;1:757–72. https://doi.org/10.1021/cbe.4c00105.

Krishnaiah D, Khiari M, Klibet F, Kechrid Z. Oxidative stress toxicity effect of potential metal nanoparticles on human cells. Toxicology: Oxidative Stress and Dietary Antioxidants 2020:107–17. https://doi.org/10.1016/B978-0-12-819092-0.00012-1.

[96] Ivan A, Pricop MA, Lukinich-Gruia AT, Cristea IM, Negrea A, Pascu IB, et al. Cellular Metabolic Responses to Copper Nanoparticles: Comparison Between Normal and Breast Cancer Cells. Int J Mol Sci 2025;26:10716. https://doi.org/10.3390/IJMS262110716/S1.

Eg H, Aa P. Copper Nanoparticles as Therapeutic Anticancer Agents. vol. 2. 2018.

Abdolmaleki S, Aliabadi A, Khaksar S. Unveiling the promising anticancer effect of copper-based compounds: a comprehensive review. J Cancer Res Clin Oncol 2024;150:213. https://doi.org/10.1007/s00432-024-05641-5.

Xiong Q, Liu A, Ren Q, Xue Y, Yu X, Ying Y, et al. Cuprous oxide nanoparticles trigger reactive oxygen species-induced apoptosis through activation of erk-dependent autophagy in bladder cancer. Cell Death & Disease 2020 11:5 2020;11:366-. https://doi.org/10.1038/s41419-020-2554-5.

Ju S, Singh MK, Han S, Ranbhise J, Ha J, Choe W, et al. Oxidative Stress and Cancer Therapy: Controlling Cancer Cells Using Reactive Oxygen Species. International Journal of Molecular Sciences 2024, Vol 25, 2024;25. https://doi.org/10.3390/ijms252212387.

Farshori NN, Siddiqui MA, Al-Oqail MM, Al-Sheddi ES, Al-Massarani SM, Ahamed M, et al. Copper Oxide Nanoparticles Exhibit Cell Death Through Oxidative Stress Responses in Human Airway Epithelial Cells: a Mechanistic Study 2011. https://doi.org/10.1007/s12011-022-03107-8.

Červinka M. The role of mitochondria in apoptosis induced in vitro. Gen Physiol Biophys 1999;18:33–40. https://doi.org/10.1146/annurev-genet-102108-134850.

Ejtema M, Chegeni N, Langen B, Ahmadi M, Zeinab M·, Seifabadi S, et al. Copper-cysteamine nanoparticles in cancer treatment: a systematic review. Cell Biology and Toxicology 2025 41:1 2025;41:158-. https://doi.org/10.1007/s10565-025-10103-w.

Abdollahzadeh H, Pazhang Y, Zamani A, Sharafi Y. Green synthesis of copper oxide nanoparticles using walnut shell and their size dependent anticancer effects on breast and colorectal cancer cell lines. Scientific Reports 2024 14:1 2024;14:20323-. https://doi.org/10.1038/s41598-024-71234-4.

Dolati M, Tafvizi F, Salehipour M, Komeili Movahed T, Jafari P. Biogenic copper oxide nanoparticles from Bacillus coagulans induced reactive oxygen species generation and apoptotic and anti-metastatic activities in breast cancer cells. Scientific Reports 2023 13:1 2023;13:3256-. https://doi.org/10.1038/s41598-023-30436-y.

He H, Zou Z, Wang B, Xu G, Chen C, Qin X, et al. Copper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells. Int J Nanomedicine 2020;15:3291–302. https://doi.org/10.2147/IJN.S241157.

Crisan MC, Teodora M, Lucian M. Copper Nanoparticles: Synthesis and Characterization, Physiology, Toxicity and Antimicrobial Applications. Applied Sciences 2022, Vol 12, 2021;12. https://doi.org/10.3390/app12010141.

Aboelella NS, Brandle C, Kim T, Ding ZC, Zhou G. Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy. Cancers (Basel) 2021;13:986. https://doi.org/10.3390/CANCERS13050986.

Boaru DL, Leon-Oliva D De, Castro-Martinez P De, Garcia-Montero C, Fraile-Martinez O, Garcيa-Gonzلlez B, et al. Cuproptosis: Current insights into its multifaceted role in disease, cancer, and translational/therapeutic opportunities. Biomedicine & Pharmacotherapy 2025;190:118422. https://doi.org/10.1016/J.BIOPHA.2025.118422.

Jiao Y, Wang H, Zhu M, Liu T, Li Y, Yang S, et al. Copper-induced cell death mechanisms and their role in the tumor microenvironment. Frontiers in Cell Death 2025;4:1628470. https://doi.org/10.3389/FCELD.2025.1628470.

Cobine PA, Brady DC. Cuproptosis: Cellular and molecular mechanisms underlying copper-induced cell death. Mol Cell 2022;82:1786–7. https://doi.org/10.1016/J.MOLCEL.2022.05.001.

Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: molecular mechanisms and health implications. Cell Res 2021;31:107–25. https://doi.org/10.1038/S41422-020-00441-1.

Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 2022;185:2401–21. https://doi.org/10.1016/j.cell.2022.06.003.

Ge EJ, Bush AI, Casini A, Cobine PA, Cross JR, DeNicola GM, et al. Connecting copper and cancer: from transition metal signalling to metalloplasia. Nature Reviews Cancer 2021 22:2 2021;22:102–13. https://doi.org/10.1038/s41568-021-00417-2.

Lin J, Luo B, Yu X, Yang Z, Wang M, Cai W. Copper metabolism patterns and tumor microenvironment characterization in colon adenocarcinoma. Front Oncol 2022;12:959273. https://doi.org/10.3389/FONC.2022.959273/FULL.

Levine B, Kroemer G. Biological Functions of Autophagy Genes: A Disease Perspective. Cell 2019;176:11–42. https://doi.org/10.1016/j.cell.2018.09.048.

Yun CW, Lee SH. The Roles of Autophagy in Cancer. Int J Mol Sci 2018;19:3466. https://doi.org/10.3390/IJMS19113466.

Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov 2022;12:31–46. https://doi.org/10.1158/2159-8290.CD-21-1059.

Pavlova NN, Thompson CB. The Emerging Hallmarks of Cancer Metabolism. Cell Metab 2016;23:27–47. https://doi.org/10.1016/j.cmet.2015.12.006.

Chen X, Chen S, Yu D. Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance. Metabolites 2020;10:289. https://doi.org/10.3390/METABO10070289.

Abbasi R, Shineh G, Mobaraki M, Doughty S, Tayebi L. Structural parameters of nanoparticles affecting their toxicity for biomedical applications: a review. Journal of Nanoparticle Research 2023;25:43. https://doi.org/10.1007/S11051-023-05690-W.

Devaraji M, Thanikachalam P V., Elumalai K. The potential of copper oxide nanoparticles in nanomedicine: A comprehensive review. Biotechnology Notes 2024;5:80–99. https://doi.org/10.1016/j.biotno.2024.06.001.

Edo GI, Ali ABM, Okolie MC, Orogu JO, Emumejaye K, Oghroro EEA, et al. Toxicity of nanostructures in drug delivery applications. Pharmaceutical Science Advances 2026;4:100117. https://doi.org/10.1016/J.PSCIA.2026.100117.

Bilardo R, Traldi F, Vdovchenko A, Resmini M. Influence of surface chemistry and morphology of nanoparticles on protein corona formation. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2022;14:e1788. https://doi.org/10.1002/WNAN.1788.

Čarapar I, Jurković L, Pavičić-Hamer D, Jaklin A, Dutour Sikirić M, Hamer B, et al. The Metal Oxidation State in Cu, CuO, and Cu2O Nanoparticles Plays a Key Role in Toxicity to Sea Urchin Arbacia lixula, Paracentrotus lividus, and Sphaerechinus granularis Embryos. Toxics 2025;13:469. https://doi.org/10.3390/TOXICS13060469.

Angelé-Martيnez C, Nguyen KVT, Ameer FS, Anker JN, Brumaghim JL. Reactive Oxygen Species Generation by Copper(II) Oxide Nanoparticles Determined by DNA Damage Assays and EPR Spectroscopy. Nanotoxicology 2017;11:278. https://doi.org/10.1080/17435390.2017.1293750.

Dincturk HC, Akkuzu N, Günal-Köroğlu D, Karaca AC, Capanoglu E. Molecular Insights into Bioactive Interactions Within Protein- and Polysaccharide-Based Colloids: Implications for Stability, Functionality, and Bioavailability. Foods 2025;15:112. https://doi.org/10.3390/FOODS15010112.

Hanna DH, Nady DS, Wasef MW, Fakhry MH, Mohamed FS, Isaac DM, et al. Plant-derived nanoparticles: Green synthesis, factors, and bioactivities. Next Materials 2025;9:101275. https://doi.org/10.1016/J.NXMATE.2025.101275.

Amjad R, Mubeen B, Ali SS, Imam SS, Alshehri S, Ghoneim MM, et al. Green Synthesis and Characterization of Copper Nanoparticles Using Fortunella margarita Leaves. Polymers (Basel) 2021;13:4364. https://doi.org/10.3390/POLYM13244364.

Liu XQ, Tang RZ. Biological responses to nanomaterials: understanding nano-bio effects on cell behaviors. Drug Deliv 2017;24:1. https://doi.org/10.1080/10717544.2017.1375577.

Mahmood RI, Kadhim AA, Ibraheem S, Albukhaty S, Mohammed-Salih HS, Abbas RH, et al. Biosynthesis of copper oxide nanoparticles mediated Annona muricata as cytotoxic and apoptosis inducer factor in breast cancer cell lines. Scientific Reports 2022 12:1 2022;12:16165-. https://doi.org/10.1038/s41598-022-20360-y.

Banerjee A, Qi J, Gogoi R, Wong J, Mitragotri S. Role of nanoparticle size, shape and surface chemistry in oral drug delivery. Journal of Controlled Release 2016;238:176–85. https://doi.org/10.1016/j.jconrel.2016.07.051.

Liu H, Guo H, Jian Z, Cui H, Fang J, Zuo Z, et al. Copper Induces Oxidative Stress and Apoptosis in the Mouse Liver. Oxid Med Cell Longev 2020;2020:1359164. https://doi.org/10.1155/2020/1359164.

Hassan AA, Sayed-Elahl RMH, Hamaky AME, Mansour MK, Oraby NH, Barakat MH. Green Synthesis of Metallic Nanoparticles and Their Biomedical Applications. Handbook of Green and Sustainable Nanotechnology: Fundamentals, Developments and Applications: Volume 1-4 2023;1:47–71. https://doi.org/10.1007/978-3-031-16101-8_4.

Huang A. Exploiting Reactive Oxygen Species in Cancer Therapy 2025. https://doi.org/10.58445/RARS.3012.

Zhou M, Tian M, Li C. Copper-Based Nanomaterials for Cancer Imaging and Therapy. Bioconjug Chem 2016;27:1188–99. https://doi.org/10.1021/ACS.BIOCONJCHEM.6B00156.

Vazquez-Muٌoz R, Borrego B, Juلrez-Moreno K, Garcيa-Garcيa M, Mota Morales JD, Bogdanchikova N, et al. Toxicity of silver nanoparticles in biological systems: Does the complexity of biological systems matter? Toxicol Lett 2017;276:11–20. https://doi.org/10.1016/j.toxlet.2017.05.007.

Dykman L, Khlebtsov N. Gold nanoparticles in biomedical applications: recent advances and perspectives. Chem Soc Rev 2012;41:2256–82. https://doi.org/10.1039/c1cs15166e.

Lim ZZJ, Li JEJ, Ng CT, Yung LYL, Bay BH. Gold nanoparticles in cancer therapy. Acta Pharmacol Sin 2011;32:983. https://doi.org/10.1038/aps.2011.82.

[140] Hheidari A, Mohammadi J, Ghodousi M, Mahmoodi M, Ebrahimi S, Pishbin E, et al. Metal-based nanoparticle in cancer treatment: lessons learned and challenges. Front Bioeng Biotechnol 2024;12:1436297. https://doi.org/10.3389/fbioe.2024.1436297.

Xu JJ, Zhang WC, Guo YW, Chen XY, Zhang YN. Metal nanoparticles as a promising technology in targeted cancer treatment. Drug Deliv 2022;29:664. https://doi.org/10.1080/10717544.2022.2039804.

Al Tamimi S, Ashraf S, Abdulrehman T, Parray A, Mansour SA, Haik Y, et al. Synthesis and analysis of silver–copper alloy nanoparticles of different ratios manifest anticancer activity in breast cancer cells. Cancer Nanotechnology 2020 11:1 2020;11:13-. https://doi.org/10.1186/S12645-020-00069-1.

Lim ZZJ, Li JEJ, Ng CT, Yung LYL, Bay BH. Gold nanoparticles in cancer therapy. Acta Pharmacol Sin 2011;32:983. https://doi.org/10.1038/aps.2011.82.

Copper nanoparticles: Synthesis, characterization, and their applications in medicine n.d. https://www.researchgate.net/publication/399274477_Copper_nanoparticles_Synthesis_characterization_and_their_applications_in_medicine (accessed February 19, 2026).

Kanninen P, Johans C, Merta J, Kontturi K. Influence of ligand structure on the stability and oxidation of copper nanoparticles. J Colloid Interface Sci 2008;318:88–95. https://doi.org/10.1016/j.jcis.2007.09.069.

Sainz V, Conniot J, Matos AI, Peres C, Zupančič E, Moura L, et al. Regulatory aspects on nanomedicines. Biochem Biophys Res Commun 2015;468:504–10. https://doi.org/10.1016/j.bbrc.2015.08.023.

Pramoda G, Verma RK, Kesharwani P, Shukla R. Surface-functionalized nanoparticles for targeted drug delivery across the blood-brain barrier: advances and challenges in neurodegenerative disease therapy. J Mol Liq 2025;433:127938. https://doi.org/10.1016/j.molliq.2025.127938.

Swaminathan N, Sharon M. Hybrid Nanomaterials for Biomedical Applications. Nanotechnology in the Life Sciences 2025;Part F657:347–63. https://doi.org/10.1007/978-3-031-85122-3_7.

Lionadi I, Payam AF. Nanotechnology in Cancer Therapy: How Nanoparticles Are Shaping the Future of Personalized Treatment. ACS Nano Medicine 2026. https://doi.org/10.1021/acsnanomed.5c00117.