Dual Fe‐Active‐Site Engineering in MCOF Nanozymes for Synergistic and Broad‐Spectrum Antibacterial Therapy

Nanozymes have emerged as promising broad‐spectrum antibacterial agents, with metal‐covalent organic frameworks (MCOFs) being particularly notable for their peroxidase (POD)‐like and photocatalytic oxidase (OXD)‐like activities. However, conventional MCOFs suffer from unstable metal‐loading structures and low metal content. Herein, a novel MCOF is developed, termed PA‐FeFe COF, with dual Fe active sites using a one‐pot construction involving 1,10‐phenanthroline‐5,6‐dione (PA), 4,4′,4′″‐(1,3,5‐triazine‐2,4,6‐triyl)triphenylamine (TAPT), and FeCl 3 . This design achieves high Fe‐loading, significantly enhancing both POD‐like activity through Fenton‐like reactions and photocatalytic OXD‐like activity by improving electron‐hole separation efficiency. PA‐FeFe COF demonstrates exceptional antibacterial performance, achieving over 99% inhibition rates against both Gram‐positive and Gram‐negative bacteria. The dual Fe sites display complementary electronic properties and synergistically generate reactive oxygen species (ROS), while the material's strong positive charge facilitates electrostatic adsorption onto bacterial membranes, further enhancing antibacterial efficacy. Additionally, PA‐FeFe COF exhibits self‐sustaining H 2 O 2 production and maintains its antibacterial activity after five cycles. In vivo experiments using antibiotic‐resistant bacterial infected wound models confirm the material's practical potential, showing rapid wound healing, high bacterial clearance rates, and good biocompatibility. This work not only establishes a new benchmark for metal‐loading in MCOFs but also provides fundamental insights into the rational design of multifunctional nanozymes for combating antibiotic‐resistant infections.