Xiaohua Zheng, Min Chen, Xinran Wang, Junjie Wu, Xiaohui Wang, Jiayi Chen, Shanmei Wang, Mengjiao Zhou, Weiqi Wang, Rui Xia
Covalent organic frameworks (COFs) offer structural tunability and intrinsic porosity, yet precise nanoscale fabrication of COF-based photosensitizers remains challenging. In this study, we report a mixed-solvent-mediated one-pot strategy to synthesize chlorin (TPC)-incorporated COF nanoparticles with tunable size by adjusting solvent composition and TPC feed ratio. Azo-based ligands confer hypoxia sensitivity to the framework. The optimized TPCCOF morphology was used to load tirapazamine (TPZ), forming the biocompatible TPCCOF@TPZ nanoplatform. Upon light irradiation, TPCCOF@TPZ enables concurrent photodynamic (PDT) and photothermal therapy (PTT). PDT exacerbates tumor hypoxia, triggering TPZ release and hypoxia-activated chemotherapy. This synergistic PDT/PTT/chemotherapy combination effectively suppresses 4T1 tumor cell proliferation under both normoxic and hypoxic conditions. Our work advances nanoscale COF design for multimodal cancer therapy and supports preclinical development of porphyrin-based photosensitizers.