Boswellic Acid-Integrated Chitosan Hybrid Nanogels for pH-Responsive Sustained Sunitinib Release and Lung Tumor Suppression

Stimuli-responsive chitosan-based nanogels have attracted significant interest for drug delivery; however, many reported systems rely on synthetic crosslinkers and function primarily as passive carriers with limited control over network architecture and molecular transport. Here, we report a boswellic-acid-integrated, pH-responsive hybrid nanogel platform in which boswellic acid serves as a bioactive network modifier and hydrophobic domain-forming component within chitosan matrices. Chitosan-boswellic acid (CS-g-BOS) hydrogel precursors were first formed via formaldehyde-assisted network formation and subsequently converted into CS-g-BOS nanogels via STPP-mediated ionic condensation, yielding a shear-thinning porous hydrogel precursor and pH-responsive nanogels relevant to injectable formulation development. The triterpenoid constituents of BOS contribute to the formation of a heterogeneous network, introducing hydrophobic domains that regulate mesh size and diffusion pathways. Comprehensive physicochemical characterization (1H NMR, FTIR, SEM, AFM, DLS, zeta potential, thermal stability, and rheological analyses) showed that BOS incorporation altered nanogel morphology, swelling behavior, rheological response, and release kinetics. The nanogels exhibited high sunitinib encapsulation efficiency (95.52%) and sustained, pH-dependent drug release over 18 days, with accelerated release under acidic tumor-mimicking conditions. Among the tested kinetic models, the Korsmeyer-Peppas model provided the best fit, suggesting that sunitinib malate (SUN) release is diffusion-dominated and modulated by pH-dependent swelling of the CS-g-BOS network. In vitro studies demonstrated cytotoxic and apoptosis-inducing activity against A549 human lung cancer cells, while hemolysis assays indicated favorable blood compatibility. Mouse xenograft studies showed tumor growth suppression, and the chick CAM assay demonstrated antiangiogenic activity; however, histological alterations in the liver, lungs, and kidneys indicated that systemic safety requires further optimization. Overall, this work presents a bio-derived hybrid-network strategy that integrates nanogel network engineering, transport control, and therapeutic functionality, offering a scalable alternative to conventional chitosan nanogels for tumor-responsive drug delivery applications.