Nanoscale Metal-Organic Framework Leveraging Water, Oxygen, and Hydron Peroxide to Generate Reactive Oxygen Species for Cancer Therapy

Abstract

Spatiotemporally increasing intracellular reactive oxygen species (ROS) level represents a promising and effective antitumor approach, but is significantly hindered by insufficient ROS sources within the tumor. Herein, a Cu-porphyrin based nanoscale metal-organic framework (nMOF) Cu^IIMOF is reported, which inherently integrates chemodynamic therapy (CDT), photodynamic therapy (PDT), and photocatalytic capabilities to generate intracellular ROS storm for cancer immunotherapy. Unlike conventional porphyrin-based MOFs, Cu^IIMOF features nearly orthogonally aligned porphyrin skeletons, minimizing π–π stacking and preventing ROS self-quenching. The Fenton-like reaction of Cu^IIMOF depletes glutathione (GSH) and catalyzes H₂O₂ to generate hydroxyl radical (·OH) for CDT. Intriguingly, its unique topology and energy levels enable Cu^IIMOF to photocatalyze the splitting of H₂O into ·OH, overcoming the limitations of oxygen/H₂O₂ dependence in PDT and CDT. Moreover, the reduced Cu^ICu^IIMOF, formed during the Fenton-like reaction, exhibits further enhanced lighted-triggered ROS generation. Thus, the developed Cu^IIMOF and Cu^ICu^IIMOF nanosheets can utilize H₂O₂, O₂, and H₂O as the source to generate a remarkable intracellular ROS storm through a synergetic CDT/PDT/photocatalytic combination. Both in vitro and in vivo experiments further demonstrate that the spatiotemporally generated ROS could effectively provoke ferroptosis and immunogenic cell death, eliciting substantial anti-tumor immune response for cancer immunotherapy.