ROS‐Responsive Nanoparticle Delivery of Dexmedetomidine Protects the Gut Vascular Barrier After Intestinal Ischemia/Reperfusion via the HDAC‐H3K27ac‐TCF4 Axis

Intestinal ischemia/reperfusion (I/R) disrupts the gut vascular barrier (GVB), causing bacterial translocation and organ injury. Dexmedetomidine can protect the GVB, but its clinical use is limited by dose‑dependent cardiorespiratory depression. To address this, we develop reactive oxygen species (ROS)‑responsive nanoparticles for targeted intestinal delivery and evaluate the efficacy and mechanism of dexmedetomidine‑loaded nanoparticles (Dex‑NPs) against intestinal I/R‑induced GVB damage. We observe that GVB disruption in clinical and experimental specimens is associated with reduced expression of Claudin5 and VE‑cadherin. Dex‑NPs preferentially accumulate in the ischemic intestine and release the drug upon ROS stimulation. Low‑dose Dex‑NPs (dexmedetomidine 5 µg/kg) confer GVB and hepatic protection comparable to high‑dose free dexmedetomidine, without detectable acute cardiorespiratory depression under the conditions tested. Mechanistically, dexmedetomidine inhibits histone deacetylase (HDAC), enhances H3K27 acetylation, and upregulates T-cell factor 4 (TCF4, encoded by TCF7L2), which directly binds and activates CLDN5 and CDH5 promoters, thereby restoring Claudin5/VE‑cadherin expression and GVB integrity; TCF4 knockdown largely abolishes these protective effects. In summary, ROS‑responsive Dex‑NPs enable low‑dose dexmedetomidine to preserve GVB integrity and mitigate post‑I/R liver injury via HDAC inhibition and TCF4 upregulation, circumventing dose‑limiting toxicity and suggesting TCF4 as a potential therapeutic target in oxidative stress‑associated gut endothelial barrier dysfunction.