pH-responsive cationic polymer-functionalized poly-ε-caprolactone microspheres scavenge cell-free-DNA to alleviate intestinal ischemia/reperfusion injury by inhibiting M1 macrophage polarization.

Intestinal ischemia/reperfusion (I/R) injury is a common life-threatening condition. Inflammatory dysregulation plays a crucial role in the pathological progression of intestinal I/R injury, indicating that controlling excessive inflammatory responses can be an effective strategy for mitigating I/R injury. Herein, after establishing a correlation between cell-free DNA (cfDNA) levels and postoperative inflammatory factors in samples from patients with intestinal I/R, we tested a cfDNA-scavenging approach for the treatment of intestinal I/R injury. Poly-ε-caprolactone (PCL) microspheres (Micro DEA2k) functionalized with a pH-responsive cationic polymer (DEA2k) to efficiently scavenge cfDNA were synthesized and evaluated.These microspheres exhibited enhanced cfDNA adsorption under inflammation-induced acidic conditions, along with low toxicity, reduced non-specific protein binding, and extended peritoneal retention. In a mouse model of intestinal I/R injury, the intraperitoneal injection Micro DEA2k effectively bound cfDNA, regulated the mononuclear phagocytic system, decreased the number of M1 macrophages, suppressed inflammation, and significantly improved the survival rate of the mice. These findings suggest that cfDNA scavenging using cationic microspheres has considerable potential for alleviating intestinal I/R injury.