Unveiling a Doxorubicin‐Cytochrome P450 Electron Transfer Pathway for Synergistic Multimodal Tumor Therapy

Doxorubicin (DOX) is a clinically approved chemotherapeutic agent that exerts its cytotoxicity through DNA intercalation and topoisomerase II inhibition. However, its redox-based mechanism remains underexplored. Here, it is revealed that DOX specifically binds to the heme center of cytochrome P450 (CYP450) enzymes via its quinone moiety, enabling electron transfer that catalyzes molecular oxygen into superoxide anions (O₂ ^•-). To enhance this process, mesoporous polydopamine (mPDA) is introduced as an electron-rich scaffold, amplifying electron flow to DOX. Furthermore, L-arginine (L-Arg) is co-delivered to supply nitric oxide (NO), which reacts with O₂ ^•- to generate peroxynitrite (ONOO^-), a stable, highly cytotoxic ROS. ONOO^- further activates matrix metalloproteinase (MMP), promoting extracellular matrix degradation and facilitating drug/oxygen penetration. Moreover, the system enables multimodal tumor therapy by integrating DOX-based chemotherapy, nitric oxide (NO) gas therapy, and mPDA-mediated photothermal therapy. This work unveils a novel DOX-CYP450 electron transfer mechanism and establishes a synergistic therapeutic paradigm to overcome tumor microenvironmental barriers and enhance treatment efficacy.