A QbD-optimized magnetic MOF-chitosan nanocarrier for targeted curcumin delivery and synergistic antimicrobial...

Antimicrobial resistance and cancer represent critical global health challenges that demand smarter, targeted drug delivery strategies. This study reports the systematic design, Quality by Design (QbD)-driven optimization, and comprehensive characterization of curcumin-loaded magnetic metal-organic framework-chitosan nanocomposites (Cur/Fe₃O₄@ZIF-8@CS) as a multifunctional nanoplatform integrating pH-responsive drug release, magnetic targeting, and broad-spectrum antimicrobial activity. A Box-Behnken experimental design was employed to optimize three critical formulation variables including MOF-to-drug ratio (X ₁), chitosan concentration (X ₂), and iron oxide content (X ₃) against four predefined Critical Quality Attributes (CQAs): particle size, zeta potential, PDI, and encapsulation efficiency. The optimized nanocomposite achieved a particle size of 228.6 ± 4.7 nm, a zeta potential of +31.5 mV, a PDI of 0.218, and an encapsulation efficiency of 87.4 ± 2.3%. Successful step-by-step assembly was confirmed by DLS, ATR-FTIR of all individual components and the final composite, TEM with size-distribution mapping, and VSM magnetometry. Drug release was sustained and pH-dependent, reaching 63.8% at pH 5.5 versus 58.4% at pH 7.4 after 72 hours, following anomalous non-Fickian transport kinetics (Korsmeyer-Peppas n = 0.61). The nanocomposite exhibited potent antimicrobial activity with MIC values up to 66-fold lower than free curcumin against Escherichia coli, and 2.5- to 45-fold lower across the remaining tested organisms. A two-month physicochemical stability study conducted under long-term (25 ± 2 °C) and accelerated (40 ± 2 °C/75 ± 5% RH, ICH Q1A(R2)) conditions confirmed that all critical quality attributes remained within acceptable pharmaceutical limits, with curcumin retention of 94.6 ± 1.8% at 25 °C and 87.9 ± 2.6% at 40 °C after two months. Cytotoxicity assessment by MTT assay on L929 mouse fibroblast cells yielded IC₅₀ values of 206.65 µg mL^-1 for the blank nanocomposite (Fe₃O₄@ZIF-8@CS) and 273.15 µg mL^-1 for the curcumin-loaded formulation (Cur/Fe₃O₄@ZIF-8@CS), confirming acceptable biocompatibility at therapeutically relevant concentrations. These findings collectively establish Cur/Fe₃O₄@ZIF-8@CS as a rationally designed, multifunctional nanoplatform with significant potential for combined antimicrobial and anticancer targeted therapy.