Zinc Ferrite-Integrated Halloysite Nanotubes as a Platform for Folate-Mediated Targeted Cisplatin Delivery

Halloysite nanotubes (HNTs), composed of an aluminosilicate framework, are naturally abundant, biocompatible, and sustainable clay minerals with a tubular morphology and tunable surface chemistry, making them attractive platforms for targeted, multifunctional drug delivery systems. In this study, a zinc ferrite integrated halloysite nanocomposite (ZnFe₂O₄/HNT) was developed via a one-pot synthesis approach for sustained release of cisplatin (Cp), aiming to reduce systemic toxicity and enhance cell-specific activity. The nanocomposites were further functionalized by integrating Cp (Cp: ZnFe₂O₄/HNT ratio 0.05) and folic acid (ZnFe₂O₄/HNT/Cp: FA ratio 0.05), followed by PEGylation (0.17 µL/mg of ZnFe₂O₄/HNT/Cp/FA/PEG). The structural and surface characteristics, phase, interfacial interactions (FA and Cp), and colloidal stability of nanoformulations were systematically investigated using powder X-ray diffraction analysis (XRD), Fourier transformed infrared (FT-IR) spectroscopy, zeta potential analysis, scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS), high-resolution transmission electron microscopy (HRTEM), and diffuse reflectance UV-visible (DRS-UV-Vis) spectroscopy. The results confirmed that ZnFe₂O₄ integration preserved the clay's tubular framework while inducing nanocrystallization of both ferrite and cisplatin, indicating molecular dispersion within the clay matrix. Functionalization with FA (ZnFe₂O₄/HNT/Cp/FA) promoted amide bond linkage, modulated Cp-FA interactions, and significantly enhanced cumulative Cp release compared to the non-functionalized system ZnFe₂O₄/HNT/Cp (10.3% at 72 h vs. 34.4% at 72 h) under tumor acidic conditions (pH 6.6). PEGylation maintained the controlled release profile while improving dispersion stability. In vitro cytotoxicity studies revealed that FA-conjugated nanocomposites exhibited enhanced, time-dependent anticancer activity against HeLa cervical cancer cells, with reduced toxicity toward normal fibroblasts, indicating preferential cellular uptake via folate receptor-mediated mechanism. Overall, this work demonstrates that FA-functionalized ZnFe₂O₄/HNT nanocomposite provides an effective clay-based platform for modulating Cp release and enhancing folate receptor protein-mediated targeted therapy for cervical cancer.