Modified zinc-doped manganese ferrite ceramic nanozymes for multimodal therapy of hepatocellular carcinoma

Hepatocellular carcinoma presents persistent therapeutic limitations arising from tumor heterogeneity, hypoxic microenvironments, and multidrug resistance. From a ceramic materials perspective, multifunctional magnetic oxide nanozymes offer an attractive route to integrate catalytic, photothermal, and drug-delivery functionalities within a single nanostructured platform. In this work, we report the design and synthesis of hyaluronic acid–functionalized, zinc-doped manganese ferrite ceramic nanozymes loaded with doxorubicin (Zn-MnFe₂O₄@DOX@HA) for synergistic liver cancer therapy. Zinc doping was introduced to modulate the crystal chemistry and enhance the enzyme-mimetic catalytic activity of the spinel manganese ferrite nanoceramics. The nanozymes were synthesized via a hydrothermal route followed by zinc incorporation through co-precipitation, surface functionalization with hyaluronic acid for active targeting of cluster of differentiation 44 receptors, and subsequent loading of the chemotherapeutic agent doxorubicin. The resulting hybrid ceramic nanostructures exhibited efficient near-infrared light absorption and photothermal conversion, coupled with pH-responsive drug release, reaching an 80.5% cumulative doxorubicin release under mildly acidic conditions. Under near-infrared irradiation, the zinc-doped manganese ferrite nanozymes demonstrated a pronounced synergistic effect combining photothermal therapy, catalytic reactive oxygen species generation, and chemotherapy. In three-dimensional Huh-7 hepatocellular carcinoma spheroids, treatment with the multifunctional ceramic nanozymes reduced cell viability to 25.9% at a doxorubicin equivalent concentration of 8 μg mL⁻ ¹ , significantly outperforming free doxorubicin (47.9%) and unloaded nanozymes (37.0%). Mechanistic studies revealed enhanced caspase-3-mediated apoptosis, upregulation of cyclin-dependent kinase inhibitor p21, mitigation of hypoxia, and downregulation of the adenosine triphosphate–binding cassette subfamily B member 1 drug efflux transporter. In conclusion, this study demonstrates how compositional doping, surface functionalization, and nano-architectural control of ceramic ferrite materials can be exploited to create intelligent, multifunctional nanozymes for bioactive and therapeutic applications, highlighting the potential of advanced oxide ceramics in cancer nanomedicine.