pH-sensitive gelatin–montmorillonite–cerium oxide nanocarriers for controlled quercetin delivery and machine learning release prediction

In this study, a novel pH-responsive hybrid nanocarrier with a water-in-oil-in-water (W/O/W) emulsion structure was developed using gelatin (G) as a biocompatible polymer, montmorillonite (MMT) as a layered diffusion barrier, and cerium oxide nanoparticles (CeO₂) as a multifunctional stabilizing agent for pH-responsive and controlled delivery of quercetin (QC). The nanocarriers were synthesized via a double-emulsion method and comprehensively characterized by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), and dynamic light scattering (DLS) with zeta potential analysis. The optimized G/MMT/CeO 2 @QC nanocarriers exhibited a uniform nanoscale size (39.3 nm) and a high negative zeta potential (− 38.6 mV), indicating excellent colloidal stability. Incorporation of MMT and CeO₂ significantly enhanced drug loading and encapsulation efficiency (43.0% and 84.5%, respectively) compared to the MMT-free G/CeO₂@QC system, due to synergistic effects of layered silicate confinement, gelatin-mediated hydrogen bonding, and CeO 2 -driven Lewis acid–base coordination. In vitro release studies demonstrated pronounced pH sensitivity, with sustained release at physiological pH (60% at pH 7.4 after 96 h) and accelerated release under tumor-mimicking acidic conditions (95% at pH 5.4). To further interpret the release kinetics, machine learning-assisted, shape-constrained data analysis was employed to provide time-resolved and physically consistent insights into pH-dependent release behavior. Kinetic modeling confirmed Higuchi and Korsmeyer–Peppas-controlled diffusion mechanisms. Cytocompatibility and anticancer activity were evaluated using the MTT assay on A549 lung cancer cells and L929 fibroblasts. Blank nanocarriers were non-toxic (> 95% cell viability), while drug-loaded nanocarriers achieved selective cytotoxicity (A549 viability reduced to 55% with 93% viability in L929 cells), outperforming free QC. Overall, this tri-component hybrid system provides a multifunctional nanoscale platform with controlled drug release, high encapsulation efficiency, and tumor-selective cytotoxicity, demonstrating strong potential as a pH-responsive nanocarrier for lung cancer therapy.