Bifunctional Nanozymes for Synergistic Treatment by Boosting Oxidative Stress and Regulating the Protein Kinase B Pathway

Although small-molecule AKT inhibitors can enhance chemosensitivity, their systemic activity frequently disrupts normal metabolic processes and causes severe side effects. Here, we report an “all-in-one” catalytic nanodrug that integrates a dual-enzyme-mimicking nanozyme (GPMM) with doxorubicin (Dox) to overcome these limitations.

GPMM simultaneously exhibits peroxidase (POD)-like and phosphatase-like activities, enabling two synergistic biochemical actions: (i) amplification of reactive oxygen species (ROS) through tumor-microenvironment-responsive catalytic conversion of endogenous hydrogen peroxide (H₂O₂), and (ii) depletion of intracellular nicotinamide adenine dinucleotide (NADH) to weaken antioxidant defenses. This dual modulation induces persistent oxidative stress and leads to precise inhibition of AKT phosphorylation, functioning as an effective and safer alternative to conventional AKT inhibitors.