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 ^II MOF 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 ^II MOF features nearly orthogonally aligned porphyrin skeletons, minimizing π–π stacking and preventing ROS self‐quenching. The Fenton‐like reaction of Cu ^II MOF depletes glutathione (GSH) and catalyzes H ₂ O ₂ to generate hydroxyl radical (·OH) for CDT. Intriguingly, its unique topology and energy levels enable Cu ^II MOF to photocatalyze the splitting of H ₂ O into ·OH, overcoming the limitations of oxygen/H ₂ O ₂ dependence in PDT and CDT. Moreover, the reduced Cu ^I Cu ^II MOF, formed during the Fenton‐like reaction, exhibits further enhanced lighted‐triggered ROS generation. Thus, the developed Cu ^II MOF and Cu ^I Cu ^II MOF nanosheets can utilize H ₂ O ₂ , O ₂ , and H ₂ O 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.