Molecular Photoswitching Unlocks Glucose Oxidase for Synergistically Reinforcing Fenton Reactions for Antitumor Chemodynamic Therapy

Abstract We have developed a new type of nanoparticles with potent antitumor activity photoactivatable via the combination of molecular photoswitching of spiropyran (SP) and enzymatic reaction of glucose oxidase (GOx). As two key processes involved therein, Fe(III)‐to‐Fe(II) photoreduction in Fe(III) metal–organic frameworks (MOFs) brings about the release of free Fe 2+ /Fe 3+ while the photoswitching of SP to merocyanine (MC) unlocks the enzymatic activity of GOx that was pre‐passivated by SP. The release of free Fe 3+ boosts its hydrolysis and therefore enables the acidification of microenvironment, which is further reinforced by one of the products of the GOx‐mediated glucose oxidation reaction, gluconic acid (GlcA). Based on the generation of Fe 2+ and acidic milieu together with another product of the oxidation reaction, hydrogen peroxide (H 2 O 2 ), these two processes jointly present triple enabling factors for generating lethal hydroxyl radicals (⋅OH) species via Fenton reactions and therefore oxidative stress capable of inhibiting tumor. The antitumor potency of such nanoparticle is verified in tumor‐bearing model mice in vivo, proclaiming its potential as a potent and safe agent based on the unique mechanism of optically manipulating enzyme activity for synergistic antitumor therapeutics with high spatial precision, enhanced efficacy and minimized side effects.