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An emerging strategy in cancer therapy involves inducing reactive oxygen species (ROS), specifically within tumors using nanozymes. However, existing nanozymes suffer from limitations such as low reactivity, poor biocompatibility, and limited targeting capabilities, hindering their therapeutic efficacy. In response, the PdRu@PEI bimetallic nanoalloys were constructed with well-catalytic activities and effective separation of charges, which can catalyze hydrogen peroxide (H2O2) to toxic hydroxyl radical (·OH) under near-infrared laser stimulation. Through facilitating electron transfer and enhancing active sites, the enhanced peroxidase-like (POD-like) enzymatic activity and glutathione (GSH) depletion abilities of nanozymes are boosted through a simple co-reduction process, leading to promising anti-tumor activity. The electron transfer between Pd and Ru of PdRu@PEI nanoalloys contributes to POD-like activity. Then, by oxidizing endogenous overexpressed GSH, enzymatic cycling prevents GSH from consuming ROS. Furthermore, the surface plasmon resonance effect of near-infrared laser on bimetallic nanoalloys ensures its photothermal performance and its local heating, further promoting POD-like activity. The integrated multi-modal therapeutic approach of PdRu@PEI has demonstrated significant anti-cancer effects in vivo studies. The nanozymes exhibit high catalytic efficiency and excellent biocompatibility, offering valuable insights for the development of nano-catalysts/enzymes for biomedical applications.

Introduction: Reactive oxygen species (ROS)-mediated therapies have typically been considered as noninvasive tumor treatments owing to their high selectivity and efficiency. However, the harsh tumor microenvironment severely impairs their efficiency.Methods: Herein, the biodegradable Cu-doped zeolitic imidazolate framework-8 (ZIF-8) was synthesized for loading photosensitizer Chlorin e6 (Ce6) and CaO2 nanoparticles, followed by surface decoration by hyaluronic acid (HA), obtaining HA/CaO2-Ce6@Cu-ZIF nano platform.Results and Discussion: Once HA/CaO2-Ce6@Cu-ZIF targets tumor sites, the degradation of Ce6 and CaO2 release from the HA/CaO2-Ce6@Cu-ZIF in response to the acid environment, while the Cu2+ active sites on Cu-ZIF are exposed. The released CaO2 decompose to generate hydrogen peroxide (H2O2) and oxygen (O2), which alleviate the insufficiency of intracellular H2O2 and hypoxia in tumor microenvironment (TME), effectively enhancing the production of hydroxyl radical (•OH) and singlet oxygen (1O2) in Cu2+-mediated chemodynamic therapy (CDT) and Ce6-induced photodynamic therapy (PDT), respectively. Importantly, Ca2+ originating from CaO2 could further enhance oxidative stress and result in mitochondrial dysfunction induced by Ca2+ overloading.Conclusion: Thus, the H2O2/O2 self-supplying and Ca2+ overloading ZIF-based nanoplatform for cascade-amplified CDT/PDT synergistic strategy is promising for highly efficient anticancer therapy.