Sacral Neural Crest‐Derived Extracellular Vesicles Promote Pelvic Ganglion Repair Through Anti‐Pyroptotic Effects Involving ANXA1–FPR2 Signaling

Abstract

ABSTRACT Pelvic autonomic nerve injury is a major cause of postoperative bowel dysfunction, yet effective strategies for restoring damaged pelvic ganglia remain lacking. Here, we demonstrate that extracellular vesicles derived from human pluripotent stem cell‐derived sacral neural crest cells (Sacral NC‐EVs) promote pelvic neuroregeneration by suppressing oxidative stress‐induced pyroptosis. In a rat model of major pelvic ganglion (MPG) injury, local administration of Sacral NC‐EVs improved gastrointestinal motility and partially restored rectal neural innervation and epithelial barrier integrity. Mechanistic analyses showed that MPG injury increased oxidative stress and activated the NLRP3‐caspase‐1‐GSDMD pyroptosis pathway, whereas Sacral NC‐EVs attenuated both responses. Comparisons across EV sources showed that Sacral NC‐EVs more effectively suppressed oxidative stress and pyroptosis and increased PGP9.5‐positive and ChAT‐positive neuronal areas than mesenchymal stem cell‐derived EVs and vagal neural crest‐derived EVs. Proteomic and functional analyses implicated EV‐associated annexin A1 (ANXA1) as one contributor to the antioxidant and anti‐pyroptotic effects of Sacral NC‐EVs through FPR2 signaling. Collectively, our findings support Sacral NC‐EVs as a promising cell‐free strategy for pelvic neural repair by targeting the oxidative stress‐pyroptosis axis.