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

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.