Sacral Neural Crest-Derived Extracellular Vesicles Suppress Pyroptosis via the ANXA1-FPR2 Axis to Repair Pelvic Ganglia

Here, we demonstrate that extracellular vesicles derived from human pluripotent stem cell–induced 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.

Mechanistically, MPG injury induced a hypoxia-associated oxidative microenvironment that activated the NLRP3–caspase-1–GSDMD pyroptosis pathway, whereas Sacral NC-EVs effectively attenuated oxidative stress and inhibited pyroptotic signaling. Comparative analyses showed that Sacral NC-EVs produced more pronounced overall therapeutic effects than mesenchymal stem cell–derived and vagal neural crest–derived EVs, highlighting a functional advantage of developmental lineage matching.