ZnO-Based Nanoparticles for Targeted Cancer Chemotherapy and the Role of Tumor Microenvironment: A Systematic Review

Abstract

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.

Keywords: cancer; nanoparticles; oncology; targeted chemotherapy; zinc.

Figure 1

PRISMA flow chart.

Figure 2

Simplified approach of nanoparticle composition and synthesis methods. ZnO: zinc oxide; NP: nanoparticle; FA: folic acid; HA: hyaluronic acid; MSN: Mesoporous silica nanoparticle; ZIF: zeolitic imidazolate framework-90; DOX: doxorubicin; 5-FU: 5-Fluorouracil; DTX: docetaxel.

Figure 3

Summary of anticancer action mechanisms of ZnO nanoparticles for achieving targeted chemotherapy.

Figure 4

Risk of bias and applicability concerns with the use of the SYRCLE risk of bias tool for the quality assessment of animal studies. (A) Authors’ judgements regarding specific domains in eligible studies. Green and red indicate “low” and “high” risk of bias, respectively, while blank cells represent “unclear” risk of bias. (B) Overall summary of applicability concerns, with each domain shown as a percentage across included studies. The blank part in each bar represents an “unclear” applicability concern.