Donor-Engineered Covalent Organic Framework Nanophotocatalysts Enabling an Oxygen-Independent Radical Storm for Hypoxic Cancer Phototherapy

Type-I photosensitizers offer significant potential for oxygen-independent photodynamic therapy (PDT) against hypoxic tumors but are often limited by inefficient reactive oxygen species (ROS) generation. Herein, we report donor–acceptor covalent organic frameworks (DACOFs) engineered as high-efficiency nanophotocatalysts to overcome this limitation. Through donor motif optimization, DACOFs achieve enhanced photophysical properties, high photostability, and reduced aggregation-induced quenching, thereby boosting ROS generation for potent type-I PDT. Crucially, type-I ROS production efficiency increases significantly with the electron-donating strength of the donor motifs. Using porphyrin as the chromophoric acceptor and phenylenediamine as the optimal donor, DACOFs exhibit exceptional electron transfer efficiency and charge carrier separation kinetics. This enables highly efficient photocatalysis of oxygen reduction and water oxidation, continuously generating massive superoxide anion radicals (O₂^•–) and hydroxyl radicals (^•OH) under hypoxic conditions during light irradiation with stable output maintained for over 1 h. As compared with the commercial type-I photosensitizer methylene blue (MB), DACOF-3 nanophotocatalysts can induce 1.61-fold higher ROS production under light irradiation for 1 h. The resulting persistent radical storm triggers synergistic apoptosis–ferroptosis in tumor cells, achieving excellent tumor inhibition even in large hypoxic tumors. These findings demonstrate donor-engineered DACOFs as a robust platform for high-performance type-I PDT.