A TME-Responsive Oxygen-Self-Supplying Hybridized Polymersome for Synergistic Triple-Modal Therapy and Precision Theranostics in Hypoxic Tumors

Abstract

This investigation addresses the pressing concern of tumor hypoxia, a phenomenon that significantly compromises the efficacy of photodynamic therapy (PDT) and chemotherapy in oncological treatment. This investigation presents a novel polymersome-based system, denoted as IR808/DOX@Psome/MnO₂, which concurrently mitigates tumor hypoxia and enables triple-modal therapy, encompassing PDT, chemodynamic therapy (CDT), and chemotherapy, alongside dual-modality imaging capabilities for precise cancer treatment. Activated by the acidic and glutathione-rich tumor microenvironment (TME), MnO₂ nanoenzymes first catalyze the conversion of H₂O₂ to O₂, which reduces hypoxia and generates cytotoxic hydroxyl radicals (·OH) and enhances CDT. The concurrent release of IR808 and doxorubicin (DOX) ensures spatiotemporally synchronized triple-modal therapy. It not only improves the efficacy of photodynamic therapy but also reverses chemotherapy resistance by inhibiting the drug efflux pathway. Furthermore, the system's activatable magnetic resonance imaging (MRI) and fluorescence imaging capabilities facilitate real-time visualization of tumor targeting and therapy progression, addressing a significant unmet need in precision oncology. The modular design of the platform permits customization with various therapeutic agents, thereby expanding its relevance to other diseases associated with hypoxia.