Oxygen-Adaptive Covalent Organic Framework Nanoarchitectonics with High Photothermal Conversion Efficiency for Quadruple-Modal Tumor Therapy

The complex tumor microenvironment (TME), characterized by coexisting normoxic and hypoxic regions, demands oxygen-adaptive nanomedicines for multimodal therapy. Herein, GTPZ is presented, an oxygen-adaptive covalent organic framework (COF)-based nanoplatform that can achieve quadruple-modal synergistic therapy through the integration of chemodynamic therapy (CDT), photothermal therapy (PTT), Type I/II photodynamic therapy (PDT), and hypoxia-activated chemotherapy. Remarkably, GTPZ exhibits a record-high photothermal conversion efficiency of 72% among COF-based nanomedicines, enabling spatiotemporal control over hypoxia-activated tirapazamine (TPZ) release to generate cytotoxic radicals. Besides, GTPZ dynamically adapts to oxygen gradients by activating Type II PDT in normoxia and switching to Type I PDT in hypoxia, with phototherapy-induced oxygen depletion amplifying TPZ activation, exhibiting high oxygen-adaptive ability. In MCF-7 models, GTPZ achieves high tumor suppression through synergistic lipid peroxidation, cell cycle arrest, and ferroptosis. This work provides a paradigm for designing intelligent nanomedicines capable of dynamically adapting to TME.