Engineering a Multifunctional Core–Shell Structured Cascade Nanoreactor for Augmented and Synergistic Carbon Monoxide Oncotherapy

• • In vivo 4T1 tumor-bearing mice treated with MMGZ plus 808 nm laser (2.0 W/cm², 5 min) exhibited significant tumor volume reduction (P < 0.0001) compared to PBS controls, demonstrating that the cascade nanoreactor achieves potent tumor growth inhibition through synergistic CO gas therapy, starvation, and photothermal effects. • • The nanoreactor addresses the bottleneck of insufficient endogenous H2O2 (100 μM) and acidity (pH 6.5) in the tumor microenvironment by using GOx to catalyze glucose conversion, generating gluconic acid and H2O2 to amplify MnCO activation and CO release, thereby overcoming the limited efficacy of conventional CO-releasing molecules. • • MPDA's high photothermal conversion efficiency enables localized hyperthermia upon 808 nm laser irradiation, which not only directly induces photothermal damage but also intensifies CO release, providing a trimodal therapeutic effect that enhances overall anticancer efficacy. • • The core-shell design with ZIF-8 encapsulation protects GOx from degradation during circulation and enables tumor-specific release, mitigating off-target CO poisoning risks associated with direct MnCO-H2O2 reactions, as evidenced by the significant antitumor effect and safety profile in the in vivo study.