eGFP tagged ZnO nanoparticles from glioblastoma targeting ferroptosis and MRP1 in head and neck squamous cell carcinoma

Abstract Background 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. Methods 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. Results 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). Conclusion 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.