{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:17:56Z","timestamp":1792793876008,"version":"4.5.0"},"reference-count":48,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cancer, a leading global cause of death responsible for nearly 10 million deaths annually, demands innovative therapeutic strategies. Intrinsic cytotoxicity and biocompatibility of zinc oxide nanoparticles (ZnO-NPs) have rendered them promising nanoplatforms in oncology. We herein systematically review their applications for targeted cancer chemotherapy, with a focus on physicochemical properties, drug delivery mechanisms, and interactions with the tumor microenvironment (TME). We searched PubMed, SCOPUS, and Web of Science from inception through December 2024 for peer-reviewed preclinical studies on cancer models. Results were qualitatively synthesized. Quality was assessed with the SYRCLE risk of bias tool. Among 20 eligible studies, ZnO-NPs were frequently functionalized with ligands to enhance tumor targeting and minimize systemic toxicity. Chemotherapeutic agents (doxorubicin, 5-fluorouracil, docetaxel, cisplatin, gemcitabine, and tirapazamine) were loaded into ZnO-based carriers, with improved anticancer efficacy compared to free drug formulations, particularly in multidrug-resistant cell lines and in vivo murine xenografts. The mildly acidic TME was exploited for pH-responsive drug release, premature leakage reduction, and improvement of intratumoral accumulation. Enhanced therapeutic outcomes were attributed to reactive oxygen species generation, zinc ion-mediated cytotoxicity, mitochondrial dysfunction, and efflux pump inhibition. Deep tumor penetration, apoptosis induction, and tumor growth suppression were also reported, with minimal toxicity to healthy tissues. ZnO-NPs might constitute a versatile and promising strategy for targeted cancer chemotherapy, offering synergistic anticancer effects and improved safety profiles. Future studies emphasizing long-term toxicity, immune responses, and scalable production could lead to clinical translation of ZnO-based nanomedicine in oncology.<\/jats:p>","DOI":"10.3390\/ijms26178417","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T16:42:21Z","timestamp":1756485741000},"page":"8417","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["ZnO-Based Nanoparticles for Targeted Cancer Chemotherapy and the Role of Tumor Microenvironment: A Systematic Review"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5651-7082","authenticated-orcid":false,"given":"Vasilis-Spyridon","family":"Tseriotis","sequence":"first","affiliation":[{"name":"Department of Neurology, Agios Pavlos General Hospital of Thessaloniki, Leoforos Ethnikis Antistaseos 161, Kalamaria, 55134 Thessaloniki, Greece"},{"name":"Laboratory of Clinical Pharmacology, Aristotle University Campus, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Ampazis","sequence":"additional","affiliation":[{"name":"Respiratory Department, Cavan & Monaghan Hospital, HSE\/RCSI, H12Y7W1 Cavan, Ireland"},{"name":"RCSI University of Medicine & Health Sciences, 123 St. Stephen\u2019s Green, Dublin D02 YN77, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6309-8410","authenticated-orcid":false,"given":"Sofia","family":"Karachrysafi","sequence":"additional","affiliation":[{"name":"Research Team \u201cHistologistas\u201d, Interinstitutional Postgraduate Program \u201cHealth and Environmental Factors\u201d, Department of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"},{"name":"Laboratory of Histology-Embryology, Department of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0709-5407","authenticated-orcid":false,"given":"Theodora","family":"Papamitsou","sequence":"additional","affiliation":[{"name":"Research Team \u201cHistologistas\u201d, Interinstitutional Postgraduate Program \u201cHealth and Environmental Factors\u201d, Department of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"},{"name":"Laboratory of Histology-Embryology, Department of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8822-0141","authenticated-orcid":false,"given":"Georgios","family":"Petrakis","sequence":"additional","affiliation":[{"name":"Pathology Department, University General Hospital of Thessaloniki AHEPA, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3615-9745","authenticated-orcid":false,"given":"Dimitrios","family":"Kouvelas","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacology, Aristotle University Campus, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4665-4443","authenticated-orcid":false,"given":"Paraskevas","family":"Mavropoulos","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacology, Aristotle University Campus, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9306-7295","authenticated-orcid":false,"given":"Konstantinos","family":"Lallas","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9093-6998","authenticated-orcid":false,"given":"Aleksandar","family":"Si\u010d","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Belgrade, 11000 Begrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8520-2897","authenticated-orcid":false,"given":"Vasileios","family":"Fouskas","sequence":"additional","affiliation":[{"name":"International Hellenic University, 14th km Thessaloniki, Nea Moudania, 57001 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Stergiou","sequence":"additional","affiliation":[{"name":"Research Team \u201cHistologistas\u201d, Interinstitutional Postgraduate Program \u201cHealth and Environmental Factors\u201d, Department of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"},{"name":"Laboratory of Histology-Embryology, Department of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavlos","family":"Pavlidis","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Pharmacology, Aristotle University Campus, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"},{"name":"ENT-Clinic, \u201cGeorge Papanikolaou\u201d General Hospital of Thessaloniki, Leoforos Papanikolaou, Exochi, 57010 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianthi","family":"Arnaoutoglou","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurophysiology, AHEPA University Hospital of Thessaloniki, Aristotle University of Thessaloniki, Kiriakidi 1, 54636 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s13045-024-01640-8","article-title":"Global burden of cancer and associated risk factors in 204 countries and territories, 1980\u20132021: A systematic analysis for the GBD 2021","volume":"17","author":"Wu","year":"2024","journal-title":"J. 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