pH/GSH-responsive dual chitosan/PLA-coated cobalt ferrite nanoparticles for targeted and selective quinidine delivery in hepatocellular carcinoma

Drug repurposing using smart nanocarriers may help overcome chemoresistance and poor tumor selectivity in hepatocellular carcinoma (HCC). Here, a pH/GSH-responsive dual chitosan/polylactic acid coated cobalt ferrite nanoparticle system (QL-CS/PLA-CFO NPs) has been explored to deliver QL for treating HCC. QL-CS/PLA-CFO NPs were prepared via ionotropic gelation and w/o/w emulsion with high loading (64.8%) and excellent stability (+28.0 mV). Comparative formulations, chitosan-only QL-CS-CFO (50.9%, −10.5 mV) and nonmagnetic QL-CS/PLA (60.7%, −21.0 mV), elucidated the roles of coating architecture and magnetic core. QL-CS/PLA-CFO NPs released 10.8% at pH 7.4 versus ∼95% at pH 4.5 with 10 mM GSH over 180 h, following quasi-Fickian diffusion kinetics. Encapsulation increased the WI38/HepG2 IC₅₀ ratio from 1.12 to 1.93 through controlled endosomal release and protecting normal cells, with ∼1.2% hemolysis and enhanced DPPH antioxidants IC₅₀ (47.9 vs. 71.9 μg/mL for free QL). DNA-binding studies revealed PLA-CFO synergy, yielding 38-fold enhanced affinity versus free QL through a minor-groove binding mode. Molecular docking suggested a potential interaction between quinidine and the HCC-associated biomarker glypican-3 (PDB 3GJB), supporting future investigation of its biological relevance. QL-CS/PLA-CFO NPs represent a promising platform for selective QL delivery in HCC, warranting further in vivo evaluation. Developed pH/GSH-responsive QL-CS/PLA-CFO nanoparticles with 64.8% quinidine loading and +28.0 mV stability for targeted HCC therapy.Achieved ∼95% selective drug release under intracellular conditions (pH 4.5 + 10 mM GSH) vs. 10.8% at physiological pH 7.4.Enhanced therapeutic index to 1.92 in HepG2/WI38 cells, with superior antioxidant activity (DPPH IC50 = 47.9 μg/mL) and low hemolysis (<1.2%).Strongest DNA minor-groove binding affinity demonstrated through PLA-CFO synergy, supporting effective anticancer action, validated by docking to B-form DNA and glypican-3.PLA-cobalt ferrite synergy outperforms single-coating/nonmagnetic formulations in stability, release control, and tumor selectivity. Developed pH/GSH-responsive QL-CS/PLA-CFO nanoparticles with 64.8% quinidine loading and +28.0 mV stability for targeted HCC therapy. Achieved ∼95% selective drug release under intracellular conditions (pH 4.5 + 10 mM GSH) vs. 10.8% at physiological pH 7.4. Enhanced therapeutic index to 1.92 in HepG2/WI38 cells, with superior antioxidant activity (DPPH IC50 = 47.9 μg/mL) and low hemolysis (<1.2%). Strongest DNA minor-groove binding affinity demonstrated through PLA-CFO synergy, supporting effective anticancer action, validated by docking to B-form DNA and glypican-3. PLA-cobalt ferrite synergy outperforms single-coating/nonmagnetic formulations in stability, release control, and tumor selectivity.