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

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.