Umbilical Cord Blood–Derived Extracellular Vesicles Enhance Neurovascular Regeneration and Improve Erectile Function in a Mouse Model of Bilateral Cavernous Nerve Injury

BACKGROUND: Erectile dysfunction (ED) secondary to cavernous nerve injury (CNI), such as that occurring after radical prostatectomy, remains a significant clinical challenge, particularly among patients who do not respond to phosphodiesterase Type 5 inhibitors (PDE5i). Extracellular vesicles (EVs) derived from umbilical cord blood (UCB) have recently emerged as a promising cell-free therapeutic modality owing to their potent regenerative and anti-inflammatory properties. OBJECTIVE: This study aimed to investigate the therapeutic efficacy of UCB-derived EVs (UCB-EVs) in restoring erectile function in a bilateral CNI mouse model. METHODS: UCB-EVs were isolated and characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Their neuroregenerative effects were assessed in vitro using Neuro-2a (N2a) cell migration assays and ex vivo by evaluating neurite outgrowth in major pelvic ganglia (MPG) and dorsal root ganglia (DRG). In vivo, fluorescently labeled UCB-EVs were tracked following intracavernous administration, and erectile function was quantified using maximal ΔICP and baseline-corrected total ΔICP during cavernous nerve stimulation. Histological and biochemical analyses were conducted to assess neurovascular integrity, apoptosis, proliferation, oxidative stress, and activation of PI3K/AKT signaling in penile tissues. RESULTS: UCB-EVs significantly enhanced N2a cell migration in vitro and promoted neurite sprouting in MPG and DRG explants ex vivo. In CNI mice, intracavernous administration of UCB-EVs resulted in dose-dependent recovery of erectile function, as demonstrated by significant increases in maximal ΔICP and baseline-corrected total ΔICP during cavernous nerve stimulation. Biodistribution analysis demonstrated preferential localization of UCB-EVs to the penile neurovascular bundle. Histological and molecular evaluations revealed preservation of endothelial and neuronal populations, suppression of apoptosis, enhanced cellular proliferation, attenuation of reactive oxygen species (ROS) accumulation, and activation of PI3K/AKT signaling pathways in UCB-EV-treated mice. DISCUSSION AND CONCLUSION: UCB-EVs promote neurovascular regeneration, mitigate oxidative stress, and improve erectile function following CNI. These findings suggest that UCB-EVs represent a promising regenerative strategy for postprostatectomy ED, particularly in patients refractory to conventional pharmacotherapy.