Neuroblastoma‐Targeting π‐Conjugated COP Nanostructure with Multiple Enzyme‐Mimetic Actions for Sonochemodynamic Immunotherapies

Sonodynamic therapy (SDT) has emerged as a promising strategy for neuroblastoma treatment, leveraging ultrasound to induce the production of reactive oxygen species (ROS) at tumor sites, thereby enhancing the efficacy of immunotherapy. However, a major challenge in SDT is the efficiency of ROS generation, particularly in the context of hypoxia within the tumor microenvironment. Herein, inspired by the natural peroxidase, an imide-linked metal-phthalocyanine-based conjugated organic polymer (COP) (COP_TPcFe) has been designed with a well-defined π-conjugated nanostructure and peroxidase-mimetic atomic Fe-N sites for sonochemodynamic immunotherapy against neuroblastoma. This work demonstrates that COP_TPcFe can efficiently produce potent ROS (•OH and •O₂ ^-) by utilizing localized H₂O₂ and the effects of ultrasound, thereby achieving efficient and synergistic tumoricidal activity. Notably, the highly π-conjugated structure endows COP_TPcFe with excellent electron transport capabilities, enabling rapid catalysis of H₂O₂ to O₂, thus alleviating the hypoxic conditions within tumors. Moreover, by encapsulating COP_TPcFe with neuroblastoma cell membranes, this study achieveshomologous targeting of tumor cells and tissues, leading to efficient accumulation within tumor cells, mitochondrial disruption, and apoptosis. Additionally, the proposed sonochemodynamic immunotherapy effectively activates natural killer cells and reverses the immunosuppressive tumor microenvironment, thereby alleviating hypoxia and significantly enhancing the therapeutic efficacy of neuroblastoma treatment.