Self-‘cycling, boosting and propelling’ multi-functional nanoplatforms for improving tumor starvation therapy

Starvation therapy, utilizing glucose oxidase (GOx) to deplete glucose and disrupt tumor energy, has shown promise in cancer treatment. However, this approach alone is insufficient to block ATP generation in tumors. Here, we introduce a self-‘cycling, boosting and propelling’ strategy, overcoming the ‘Achilles' heel’ of traditional starvation therapy by regulating the energy supply with CO. The high concentration of H 2 O 2 in the tumor microenvironment reacts with MnO 2 to generate Mn 2+ and O 2 . Mn 2+ catalyzes a Fenton-like reaction to produce hydroxyl radicals ( OH) for chemodynamic therapy and T1-weighted magnetic resonance imaging (MRI), while O 2 further enhances GOx-mediated glucose consumption, producing more H 2 O 2 . This process not only recycles H 2 O 2 but accelerates CO release, disrupting ATP synthesis and inhibiting tumor energy supply. Additionally, the gas released enhances nanoplatform motility, improving tumor penetration and overcoming the limited permeability of conventional nanoparticles. In vitro and in vivo studies demonstrated superior antitumor and antimetastatic efficacy, coupled with excellent biocompatibility. This strategy offers a promising solution to traditional starvation therapy's challenges, with strong potential for clinical translation and transformative cancer treatment.