pH-regulated ''ON/OFF″ glucose oxidase nanoparticles for synergistic therapy and amplification of immunogenic cell death.

Although the combination of glucose oxidase (GOx)-based starvation therapy and chemodynamic therapy (CDT) has shown great potential, the severe systemic toxicity caused by the non-specific activity of GOx in the blood circulation and the insufficient immunogenic cell death (ICD) effect induced by doxorubicin (DOX) jointly restrict its clinical transformation. In this paper, an intelligent nanoplatform (GTF-DOX) integrating pH-responsive enzyme activity switch, multi-mode synergistic therapy, and immune activation is reported. Through the acid-sensitive Schiff base bond formed between 2,3,4-trihydroxybenzaldehyde (TB) and GOx, the platform realizes the 'off' of GOx activity in the blood and the specific 'on' in the tumor microenvironment, eliminating the risk of hypoglycemia from the root. At the same time, Fe3+ bridges GOx-TB and DOX to construct a compact integrated synergistic delivery system, and the cell uptake efficiency is significantly improved by DOX-mediated charge reversal and membrane penetration. Experiments have shown that GTF-DOX can cascade drive starvation therapy, high-efficiency CDT, and chemotherapy after being activated at the tumor site, resulting in a strong synergistic anti-tumor effect. The severe oxidative stress caused by this process and DOX synergistically enhances the ICD effect, successfully triggering calreticulin (CRT) exposure, high mobility group protein B1 (HMGB1), and ATP release, thereby promoting dendritic cell maturation and cytotoxic T lymphocyte infiltration, and stimulating a strong anti-tumor immune response in the 4T1 tumor-bearing mouse model. In this study, the problems of safety and synergistic efficacy were solved simultaneously through ingenious chemical design, providing a new paradigm for the development of intelligent tumor combination therapy.