Glucose Oxidase-Based pH/ROS Dual-Sensitive Nanoparticles for Tumor Starvation and Oxidative Therapy

Cancer cells with their distinct energy supply and metabolic patterns offer unique opportunities for targeted therapy development. This study presents pH/ROS dual-responsive enzyme-carrying nanoparticles for efficient starvation and oxidative therapy in cancer treatment. The nanoparticles, composed of zeolitic imidazolate framework-8 (ZIF-8), glucose oxidase (GOx), and hyaluronic acid (HA), were designed to leverage the unique metabolic characteristics of cancer cells. GOx was covalently modified onto HA to create HA-GOx, demonstrating enhanced enzymatic activity and thermal stability compared with free GOx. The nanoparticles ZIF@HAgel-GOx were then synthesized by adsorbing HA-GOx onto ZIF-8 and crosslinking with a ROS-sensitive crosslinker, acetone-[bis-(2-amino-ethyl)-dithioacetal] (TK). The enzymatic properties of ZIF@HAgel-GOx in solution and in cells were comparable to those of free GOx, and both could consume glucose to catalyze the reaction. The produced H2O2 could decrosslink the gel layer of ZIF@HAgel-GOx, and the produced gluconic acid could degrade the ZIF-8 core, eventually leading to the complete disassembly of ZIF@HAgel-GOx. Cytotoxicity assays revealed that GOx-carrying nanoparticles exhibited superior cytotoxicity to DOX carriers and could effectively eliminate cancer cells with minimal dosage. The findings provide a scientific rationale for the use of enzyme-based therapies in the treatment of various diseases.