Tailored Porous Bimetallic Nanozyme Platform for Full‐Cycle Therapeutics of Intestinal Ischemia/Reperfusion

ABSTRACT Intestinal ischemia/reperfusion (I/R) injury presents a biphasic pathology: an acute oxidative‐inflammatory phase leading to organ failure, and a recovery phase marked by mucosal dysfunction and bacterial translocation. The developed MPB@TA‐Cu‐Ma nanocomposite functions as a dual‐phase therapeutic platform with significant efficacy. It rapidly scavenges reactive oxygen species (ROS) (exhibiting a 50.15% higher clearance in vitro) and suppresses macrophage pyroptosis within 6 h post‐I/R. Furthermore, it enhances mucosal integrity (1.98‐fold Occludin upregulation) and angiogenesis (3.6‐fold increase in CD31 + cells) by 96 h. Transcriptomic and immunohistochemical analyses identify three key mechanisms underlying this efficacy: (1) inhibition of the NOD‐like receptor family pyrin domain‐containing 3 (NLRP3)/ cysteinyl aspartate‐specific proteinase 1 (caspase‐1) pathway to suppress pyroptosis; (2) upregulation of defensin alpha 1 (DEFA1) and desmoglein 1 (DSG1) for epithelial repair; and (3) enhancement of vascular endothelial growth factor (VEGF) and angiotensin‐converting enzyme (ACE) expression for vascular regeneration. Overall, MPB@TA‐Cu‐Ma achieves synchronized, phase‐adaptive therapy by disrupting the oxidative‐inflammatory‐barrier axis through enhanced ROS scavenging, enzyme‐mimetic activity, promotion of angiogenesis, and immune modulation, thereby effectively addressing the complex biphasic pathology of intestinal I/R injury.