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This research aims to develop a pH-sensitive nanocarrier system for the controlled delivery of quercetin in lung cancer therapy.

July 6, 2026Scientific Reports0 citationsOpen Access

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

MPMehrab PourmadadiShahid Beheshti University JKJafar KhanjariSharif University of Technology SSSalar Mohammadi ShabestariUniversity of Tehran

Key Points

This research aims to develop a pH-sensitive nanocarrier system for the controlled delivery of quercetin in lung cancer therapy.
Synthesized gelatin-montmorillonite-cerium oxide nanocarriers via a double-emulsion method.
Characterized using FTIR, XRD, FESEM, and DLS.
Evaluated cytocompatibility and anticancer activity in A549 lung cancer and L929 fibroblast cells.
Achieved high encapsulation efficiency of 84.5% for drug-loaded nanocarriers.
Showed selective cytotoxicity with A549 cell viability reduced to 55% and >95% viability in L929 cells.
Demonstrated sustained release of quercetin at pH 7.4 and accelerated release at pH 5.4.

Abstract

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.

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