A novel cascade enzyme/fenton reaction approach for enhanced chemodynamic and starvation therapy

This study has constructed a hyaluronic acid (HA) modified hollow mesoporous copper single-atom nanozyme HA@Cu-SAC@GOx for synergistically enhancing trimodal antitumor therapy, encompassing chemodynamic therapy, starvation therapy, and pyroptosis induction. The system employs hollow mesoporous carbon spheres as a carrier, with atomically dispersed copper single atoms through CuN₄ coordination structure. Glucose oxidase (GOx) is encapsulated within the cavity, while the surface is modified with hyaluronic acid via electrostatic adsorption, conferring targeting capability toward CD44-overexpressing tumor cells. Upon reaching the tumor microenvironment, HA is degraded by hyaluronidase (HAase), triggering the release of GOx. The released GOx catalyzes glucose oxidation to generate hydrogen peroxide (H₂O₂) while depleting adenosine triphosphate (ATP), thereby achieving starvation therapy. Simultaneously, the in situ generated H₂O₂ is efficiently converted into highly toxic hydroxyl radicals (‧OH) via Cu-SAC-mediated Fenton-like reactions under weakly acidic conditions, significantly enhancing chemodynamic therapeutic efficacy. This process also consumes substantial glutathione (GSH), disrupts the intracellular redox homeostasis, induces mitochondrial damage, and activates caspase-1, subsequently triggering GSDME-mediated pyroptosis. These interconnected mechanisms collectively generate a synergistic antitumor effect. In a 4T1 tumor-bearing mouse model, a single intravenous injection achieved an 83.6% tumor growth inhibition rate after 14 days and a 100% survival rate at 40 days, with no significant systemic toxicity observed. This study validates the potential of HA@Cu-SAC@GOx as an efficient and low-toxicity combinatorial therapeutic strategy, providing a crucial theoretical and experimental foundation for the clinical translation of single-atom nanozymes.