Development of hyaluronic acid-modified pH-responsive Cu-based nanocascade reactor for enhanced cancer...

Dynamic therapies based on reactive oxygen species (ROS) are becoming a pioneering paradigm for tumor-specific treatment. However, the self-protective mechanisms of cancer cells, particularly the overexpression of intracellular glutathione (GSH), significantly limit the therapeutic efficacy of anticancer treatments. Herein, we developed a pH-responsive nanocascade reactor (DOX@Cu-SKH) based on a copper infinite coordination polymer, which was functionalized with hyaluronic acid (HA) to deliver doxorubicin (DOX) for achieving efficient synergistic chemotherapy and chemodynamic therapy (CT/CDT). The nanocascade reactor demonstrates remarkable biological functionality, including specific tumor-targeting capability and augmented tumor accumulation through the enhanced permeability and retention (EPR) effect. Most notably, in vitro experiments have demonstrated that DOX@Cu-SKH nanoparticles (NPs) could generate large amounts of cytotoxic hydroxyl radicals (·OH) via Fenton-like reaction-mediated, causing damage to tumor cells. At the same time, sulfasalazine effectively inhibited glutathione peroxidase 4 (GPX4) activity, further amplifying oxidative stress in tumor cells. In vivo studies utilizing H22 tumor-bearing mouse model demonstrated that the combination of CT/CDT significantly suppressed tumor growth with 88.7% tumor inhibition. This study introduces a novel strategy for the direct construction of a nanocascade reactor that achieves efficient CT/CDT combination therapy.