An Electron Defect Engineering‐Based Nanoparticle to Precisely Trigger Peroxynitrite Release to Synergistically Eliminate Bacteria and Alleviate Inflammation

ABSTRACT The threat of bacterial infections such as Glaesserella parasuis and Streptococcus suis urges the development of advanced therapeutic strategies. To address this challenge, HAPC was designed with cascading responsiveness. When exposed to 640–660 nm red light, the electron‐deficient porphyrin–zirconium MOF (PCN‐224) can effectively use its natural photosensitive nature to generate reactive oxygen species (ROS) and trigger subsequent reactions. Within the acidic conditions at the infection site, arginine (Arg) was triggered to release nitric oxide (NO), which may subsequently interact with ROS to form peroxynitrite (ONOO − ) putatively contributing to enhanced antibacterial activity. The MIC for SS was just 0.25 µg/mL, making it four times more efficient than the free antibiotic CIP. Our study suggests that ONOO − potentially influenced the primary inflammatory pathway NF‐κB and decreased the transcription levels of inflammatory mediators with TNF‐α decreased by 10‐fold for and IL‐1β by 2.5‐fold for respectively, ensuring antibacterial and anti‐inflammatory responses at the same time. Experiments in vivo indicated that HAPC treatment could successfully clear bacteria from the infection site and hasten wound recovery, eventually decreasing the wound area to around 3%. This research showed that HAPC, via a proposed cascade mechanism originating from its material properties, offers a highly efficient, biosafe approach to combat zoonotic drug‐resistant bacterial infections.