Light-Activated Fluorinated Porphyrin COFs: Dual Oxygen/Drug Carriers Reshaping Tumor Hypoxia for Precision Photodynamic-Chemo Therapy

Tumor hypoxia poses a significant challenge to photodynamic therapy (PDT) by limiting the generation of oxygen-dependent reactive oxygen species (ROS). Although covalent organic frameworks (COFs) have shown potential in the biomedical field, their dual role in oxygen buffering and drug delivery has not been fully explored. To address these limitations, we engineered a fluorinated porphyrin-based COF (TT-COF) integrating hierarchical porosity and oxygen-buffering functionality for multimodal cancer therapy. Our structural optimization strategy leveraged van der Waals forces mediated by fluorinated electron-deficient motifs for enhanced oxygen retention, while host-guest interactions facilitated a high drug-loading capacity. The TT-COF@DOX-O2 nanocomposite demonstrated a synergistic effect, enhancing PDT under oxygen-rich conditions, alleviating tumor hypoxia during chemotherapy, and facilitating near-infrared (NIR)-triggered drug release. In vitro studies revealed a potent synergistic cytotoxic effect, attributed to ROS overproduction and light-activated DOX release. Furthermore, fluorescence imaging confirmed that this combinatorial oxidative and chemotherapeutic stress significantly enhanced apoptosis. In a 4T1 tumor-bearing mouse model, the TT-COF@DOX-O2 nanocomposite sustained tumor oxygenation to improve 1O2 generation while also achieving spatiotemporally controlled drug delivery, resulting in significant tumor suppression. These results position COFs as versatile nanoplatforms capable of reshaping hypoxic tumor microenvironments and facilitating precision combination therapies. This work presents a transformative approach that addresses the limitations of traditional cancer treatments and establishes a promising foundation for the clinical application of structurally programmable nanomaterials in oncology.