Glucose-oxidase-integrated zinc-based metal-organic framework (GOx@ZIF-8) nanoparticles as a dual pH/glucose-responsive insulin delivery system for type 2 diabetes management: Synthesis, characterization, and in vitro/in vivo evaluation.

Type 2 diabetes mellitus (T2DM) affects over 537 million adults worldwide; conventional insulin therapy suffers from poor oral bioavailability, enzymatic degradation, and hypoglycemia risk. We developed a dual pH- and glucose-responsive PEG-GOx@ZIF-8-Ins nanoplatform for oral insulin delivery via biomimetic co-precipitation. The optimized nanoplatform (178 ± 7.0 nm; zeta potential -26.5 ± 1.8 mV; surface area 891 m2/g) achieved 79.8 ± 2.7% encapsulation efficiency and 87.4% GOx retention. Release was minimal under gastric conditions (<10%) but reached 97.2% at 25 mM glucose, with high glucose selectivity. Cytotoxicity assays confirmed biocompatibility (IC50 > 200 μg/mL). In diabetic rats, oral bioavailability reached 7.2%, 5.5-fold higher than free insulin, with prolonged half-life, higher area under the curve (AUC), and 10-h normoglycemia without hypoglycemia. PEG-GOx@ZIF-8-Ins is a promising oral insulin delivery strategy for T2DM.