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 CaO2nanoparticles, 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 CaO2release 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 CaO2decompose to generate hydrogen peroxide (H2O2) and oxygen (O2), which alleviate the insufficiency of intracellular H2O2and 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 CaO2could further enhance oxidative stress and result in mitochondrial dysfunction induced by Ca2+overloading.Conclusion:Thus, the H2O2/O2self-supplying and Ca2+overloading ZIF-based nanoplatform for cascade-amplified CDT/PDT synergistic strategy is promising for highly efficient anticancer therapy.