Facile Preparation of Nanoscale Chlorin-Integrated Covalent Organic Frameworks for Combined Chemophototherapy

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.