ZnGlu Bio-MOF functionalized with FA-BSA for targeted quercetin delivery: High drug loading, pH-Responsive release, and enhanced anticancer activity

Herein, we developed a water-stable ZnGlu bio-metal-organic framework (Bio-MOF) composed of biocompatible zinc ions and l -glutamic acid as a green nanocarrier for the targeted delivery of quercetin (Qu), a hydrophobic natural anticancer agent. Successful loading of quercetin into ZnGlu framework was achieved by an in situ loading method with high drug loading capacity (57.8%) and loading efficiency (92.4%). To improve tumor targeting and biocompatibility, the carrier surface was modified with folic acid-conjugated bovine serum albumin (FA-BSA). Structural and morphological analyses confirmed the successful preparation of the Qu@ZnGlu@FA-BSA nanocarrier and the preservation of the framework integrity after drug loading and surface modification. The system displayed prolonged and pH-responsive drug release with enhanced quercetin release under acidic conditions mimicking the tumor microenvironment. The fluorescence microscopy revealed enhanced cellular uptake of Qu@ZnGlu@FA-BSA in MDA-MB-231 breast cancer cells, which is attributed to folate receptor-mediated endocytosis. Moreover, the MTT and Annexin V-FITC/PI assays showed increased anticancer activity and apoptosis induction as compared to free quercetin and non-functionalized Qu@ZnGlu, resulting in a low IC50 value (24.6 μg/mL) against MDA-MB-231 cells. The results of this study indicate that FA-BSA-modified ZnGlu Bio-MOFs represent a promising platform for targeted and pH-responsive quercetin delivery in cancer therapy.