Heterostructure nanozymes with sustainable tumor microenvironment regulation and reinforced hyperthermia-responsive catalytic activities for orchestrated osteosarcoma catalytic therapy

Catalytic therapy employing nanozymes has evoked extensive exploration as a promising regimen for cancer theranostics, with specific reactivity in response to tumor microenvironment (TME). However, inherently deficient catalytic efficiency and instability compromise their anticancer efficacy, thus limiting biomedical applications. Herein, we report a novel gold-based heterostructure nanozyme (ATP@IR) with dual enzymes-mimicking activities and illustrious photothermal effect for bone tumor catalytic treatment, aiming at obtaining balanced synergism of catalytic therapy and hyperthermia. With the advantage of its unique tipping-deposition heterostructure structure, ATP@IR nanozymes expedite the electron-hole pair separation and produce massive hot electron, leading to illustrious photothermal effect for tumor hyperthermia treatment. Intriguingly, ATP@IR nanozymes display both intrinsic peroxidase (POD)-mimicking (Km: 39.56 mM) and catalase (CAT)-mimicking activities under weakly acidic TME, which could breakdown endogenous H2O2 into deleterious hydroxyl radicals (·OH) and simultaneously replenish oxygen, realizing efficient tumor ablation and hypoxia alleviation. Meanwhile, elevated oxygen level is leveraged to synergistically produce more reactive oxygen species by reacting with ICG for enhanced photodynamic efficacy. Benefiting from phenomenal thermal conversion efficiency (η = 73.6 %), the dual enzyme-mimicking activities of nanozymes are dramatically improved upon mild hyperthermia when exposure to laser, which actualize hyperthermia-augmented catalytic treatment. Impressively, the potent antitumor efficacy is demonstrated by in vivo xenograft osteosarcoma models without causing lung metastasis. Accordingly, this work provides a reasonable strategy by integrating nanocatalytic treatment, hyperthermia treatment, and TME modulation for efficient treatment of osteosarcoma.