Acellular mesenchymal stem cell–derived exosomes and secretome for erectile dysfunction: a systematic review and meta-analysis of preclinical studies

Abstract

Phosphodiesterase-5 inhibitors provide symptomatic relief for erectile dysfunction (ED), but patients with neurogenic injury or long-standing diabetes may remain partial or nonresponders. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs)/exosomes and secretome/conditioned medium (CM) represent potential cell-free restorative therapies. We systematically evaluated their efficacy in preclinical ED models. PubMed and Europe PubMed Central were searched through September 1, 2025, for controlled in vivo rodent studies comparing MSC-derived EVs/exosomes or secretome/CM with model-matched ED controls. Erectile function was assessed using maximal intracavernosal pressure normalized to mean arterial pressure (ICP/MAP). Risk of bias was evaluated using the SYRCLE tool. Standardized mean differences (SMDs) were pooled using random-effects meta-analysis, with subgroup and sensitivity analyses. Thirteen studies comprising 18 comparisons (126 treated and 106 control animals) were included. MSC-derived acellular therapies significantly improved erectile function (SMD, 2.17; 95% CI, 1.48–2.87; I² = 70%). Effects were consistent in bilateral cavernous nerve injury and diabetic models. Native and engineered EVs showed no statistically significant subgroup difference. Mechanistic findings supported restoration of NO/cGMP signaling, smooth-muscle preservation, antifibrotic activity, and neuroprotective and antioxidant effects. MSC-derived EVs/exosomes and secretome/CM improve erectile function across preclinical ED models, although substantial heterogeneity and methodological reporting limitations reduce certainty. Standardized EV characterization, dosing, and functional assessment are required before clinical translation.