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.