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@HA gel -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@HA gel -GOx in solution and in cells were comparable to those of free GOx, and both could consume glucose to catalyze the reaction. The produced H 2 O 2 could decrosslink the gel layer of ZIF@HA gel -GOx, and the produced gluconic acid could degrade the ZIF-8 core, eventually leading to the complete disassembly of ZIF@HA gel -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.