Polypeptide Nanomicrospheres Delivering Dexmedetomidine Mitigate Intestinal Ischemia/Reperfusion Injury by Regulating Autophagy and Inflammation

Aims: This study aims to evaluate the protective effects of dexmedetomidine-loaded polypeptide nanomicrospheres (PNM@Dex) in a mouse model of intestinal ischemia/reperfusion (I/R) injury and investigate the underlying molecular mechanisms, focusing on autophagy activation in enteric neurons. Results: PNM@Dex, synthesized via solid-phase peptide synthesis and coprecipitation, exhibited uniform spherical morphology (∼150 nm) and high drug encapsulation efficiency. In vitro studies demonstrated that PNM@Dex promoted autophagy in enteric neurons, attenuated oxidative stress and apoptosis, and improved cell viability. In vivo administration significantly mitigated intestinal injury, suppressed inflammatory cytokine production, and increased the expression of autophagy-related proteins. Autophagy inhibition assays confirmed the essential role of autophagy in mediating the protective effects of PNM@Dex. Innovation: This study represents the first successful incorporation of dexmedetomidine into polypeptide nanomicrospheres for targeted delivery to enteric neurons. The nanoplatform achieved sustained release, enhanced autophagy, and exerted strong anti-inflammatory and antioxidant effects, offering a novel therapeutic approach for intestinal I/R injury and potential protection in intestinal transplantation. Conclusion: PNM@Dex effectively alleviated intestinal I/R-induced damage through autophagy induction, oxidative stress reduction, and inflammation modulation, underscoring its promise as a therapeutic strategy for intestinal protection and transplantation. Antioxid. Redox Signal. 44, 213–235.