Enzyme‐Empowered “Two Birds with One Stone” Strategy for Amplifying Tumor Apoptosis and Metabolic Clearance

Abstract Nanomedicine has reshaped the landscape of cancer treatment. However, its efficacy is still hampered by innate tumor defense systems that rely on adenosine triphosphate (ATP) for fuel, including damage repair, apoptosis resistance, and immune evasion. Inspired by the naturally enzymatic reaction of glucose oxidase (GOx) with glucose, here a novel “two birds with one stone” technique for amplifying enzyme‐mediated tumor apoptosis and enzyme‐promoted metabolic clearance is proposed and achieved using GOx‐functionalized rhenium nanoclusters‐doped polypyrrole (Re@ReP‐G). Re@ReP‐G reduces ATP production while increasing H 2 O 2 concentrations in the tumor microenvironment through GOx‐induced enzymatic oxidation, which in turn results in the downregulation of defense (HSP70 and HSP90) and anti‐apoptotic Bcl‐2 proteins, the upregulation of pro‐apoptotic Bax, and the release of cytochrome c. These processes are further facilitated by laser‐induced hyperthermia effect, ultimately leading to severe tumor apoptosis. As an enzymatic byproduct, H 2 O 2 catalyzes the conversion of rhenium nanoclusters in Re@ReP‐G nanostructures into rhenate from the outside in, which accelerates their metabolic clearance in vivo. This Re@ReP‐G‐based “two birds with one stone” therapeutic strategy provides an effective tool for amplifying tumor apoptosis and safe metabolic mechanisms.