Dumbbell-shaped bimetallic AuPd nanoenzymes for NIR-II cascade catalysis-photothermal synergistic therapy

The noble metal NPs that are currently applied to photothermal therapy (PTT) have their photoexcitation location mainly in the NIR-I range, and the low tissue penetration limits their therapeutic effect. The complexity of the tumor microenvironment (TME) makes it difficult to inhibit tumor growth completely with a single therapy. Although TME has a high level of H₂O₂, the intratumor H₂O₂ content is still insufficient to catalyze the generation of sufficient hydroxide radicals (‧OH) to achieve satisfactory therapeutic effects. The AuPd-GOx-HA (APGH) was obtained from AuPd bimetallic nanodumbbells modified by glucose oxidase (GOx) and hyaluronic acid (HA) for photothermal enhancement of tumor starvation and cascade catalytic therapy in the NIR-II region. The CAT-like activity of AuPd alleviates tumor hypoxia by catalyzing the decomposition of H₂O₂ into O₂. The GOx-mediated intratumoral glucose oxidation on the one hand can block the supply of energy and nutrients essential for tumor growth, leading to tumor starvation. On the other hand, the generated H₂O₂ can continuously supply local O₂, which also exacerbates glucose depletion. The peroxidase-like activity of bimetallic AuPd can catalyze the production of toxic ‧OH radicals from H₂O₂, enabling cascade catalytic therapy. In addition, the high photothermal conversion efficiency (η = 50.7 %) of APGH nanosystems offers the possibility of photothermal imaging-guided photothermal therapy. The results of cell and animal experiments verified that APGH has good biosafety, tumor targeting, and anticancer effects, and is a precious metal nanotherapeutic system integrating glucose starvation therapy, nano enzyme cascade catalytic therapy, and PTT therapy. This study provides a strategy for photothermal-cascade catalytic synergistic therapy combining both exogenous and endogenous processes. STATEMENT OF SIGNIFICANCE: AuPd-GOx-HA cascade nanoenzymes were prepared as a potent cascade catalytic therapeutic agent, which enhanced glucose depletion, exacerbated tumor starvation and promoted cancer cell apoptosis by increasing ROS production through APGH-like POD activity. The designed system has promising photothermal conversion ability in the NIR-II region, simultaneously realizing photothermal-enhanced catalysis, PTT, and catalysis/PTT synergistic therapy both in vitro and in vivo. The present work provides an approach for designing and developing catalytic-photothermal therapies based on bimetallic nanoenzymatic cascades.