Multienzyme‐Like Polyoxometalate‐Based Single‐Atom Enzymes for Cancer‐Specific Therapy Through Acid‐Triggered Nontoxicity‐to‐Toxicity Transition

Abstract Single‐atom enzymes (SAzymes) exhibit great potential for chemodynamic therapy (CDT); while, general application is still challenged by their instability and unavoidable side effects during delivery. Herein, a manganese‐based polyoxometalate single‐atom enzyme (Mn‐POM SAE) is first introduced into tumor‐specific CDT, which exhibits tumor microenvironment (TME)‐activated transition of nontoxicity‐to‐toxicity. Different from traditional POM materials, the aggregates of low‐toxic Mn‐POM SAE nanospheres are obtained at neutral conditions, facilitating efficient delivery and avoiding toxicity problems in normal tissues. Under acid TME conditions, these nanospheres are degraded into smaller units of toxic Mn(II)‐PW₁₁; thus, initiating cancer cell‐specific therapy. The released active units of Mn(II)‐PW₁₁ exhibit excellent multienzyme‐like activities (including peroxidase (POD)‐like, oxidase (OXD)‐like, catalase (CAT)‐like, and glutathione peroxidase (Gpx)‐like activities) for the synergistic cancer therapy due to the stabilized high valence Mn species (Mn^III/Mn^IV). As demonstrated by both intracellular evaluations and in vivo experiments, ROS is generated to cause damage to lysosome membranes, further facilitating acidification and impaired autophagy to enhance cancer therapy. This study provides a detailed investigation on the acid‐triggered releasing of active units and the electron transfer in multienzyme‐mimic‐like therapy, further enlarging the application of POMs from catalytical engineering into cancer therapy.