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

ABSTRACT 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.