Dendrimer-Entrapped CuPt Bimetallic Nanozymes for Tumor Microenvironment-Regulated Photothermal/Catalytic Therapy

Noble metal nanozymes have attracted extensive attention in tumor therapy due to their multiple enzyme-like activities for catalytic therapy and unique optical properties for photothermal therapy (PTT). However, their therapeutic efficiency may be compromised by the intricate tumor microenvironment (TME). Herein, copper-platinum (CuPt) bimetallic nanozymes were synthesized and entrapped by poly(amidoamine) dendrimers, with <i>p</i>-carboxybenzenesulfonamide (BS, a carbonic anhydrase IX (CA IX) inhibitor) modified on the surface and lonidamine (Lon) loaded inside to regulate TME for enhanced catalytic therapy and PTT. The formed CPL@G5-BS nanozymes could specifically target CA IX-overexpressed tumor cells and activate the cascade catalytic reaction with continuous ^•OH generation by the peroxidase-like property, O₂ supply by the catalase-like property, and H₂O₂ replenishing by the superoxide dismutase-like property, thereby alleviating hypoxia and achieving chemodynamic therapy (CDT). In the TME, BS-mediated CA IX inhibition would normalize the extracellular pH to suppress metastasis while reducing the intracellular pH to boost the catalytic efficiency, and Lon-mediated mitochondrial respiration inhibition and energy metabolic disruption would elevate intracellular oxygen accumulation and downregulate heat shock protein (HSP) expression, further enhancing the PTT efficacy. Meanwhile, the excellent photothermal performance of CPL@G5-BS could amplify the multienzyme activities, and Cu²⁺-mediated glutathione depletion further improved the CDT efficiency. Overall, the CPL@G5-BS nanozymes can efficiently inhibit tumor growth and suppress metastasis by TME-regulated catalytic therapy and PTT.