Emerging roles of stem cells and exosomes in male reproductive injury: mechanisms, engineering approaches, and therapeutic potential

Male reproductive injuries—including erectile dysfunction (ED), chemotherapy/radiotherapy-induced testicular damage, epididymal dysfunction, and oligoasthenoteratozoospermia—represent a growing global health burden. Current therapies offer limited efficacy for refractory cases. Mesenchymal stem cells (MSCs) and their small extracellular vesicles (sEVs) have emerged as promising regenerative strategies capable of repairing reproductive microenvironments through cell replacement, paracrine modulation, and immunoregulation. This review highlights sEVs, commonly referred to as exosomes in the literature, as natural nanocarriers and discusses advanced nanoengineering strategies for precision delivery. This review systematically examines therapeutic mechanisms across three organs with markedly different levels of translational maturity: (i) in the corpus cavernosum, where the most advanced evidence exists, including early-phase clinical trials, EV-associated miRNAs (miR-126-3p, miR-210-3p) and lncRNAs (MALAT1) modulate inflammation, angiogenesis, and fibrosis; (ii) in the testis, where evidence remains predominantly preclinical with limited early human data, miR-34c-3p/GDNF signaling promotes spermatogonial stem cell self-renewal, while mitochondrial transfer restores Leydig cell testosterone synthesis; and (iii) in the epididymis, a substantially more exploratory area where direct in vivo studies are scarce and most evidence is derived from in vitro or indirect observations, region-specific cargoes (USP44/RBM14, miR-199a-3p/VHL/HIF-1α, circRNAs) maintain sperm maturation and epigenetic reprogramming. Nanotechnology platforms may enhance therapeutic precision: PLGA nanoparticles prolong circulation, GelMA hydrogels enable sustained release, and magnetic soft microrobots provide enhanced targeting efficiency. Preclinical studies consistently demonstrate that MSC/exosome-based therapy significantly improves erectile function, reduces germ cell apoptosis, and increases sperm maturation. Preclinical studies consistently demonstrate that MSC/exosome-based therapies improve functional recovery through paracrine mechanisms, anti-inflammatory effects, and promotion of angiogenesis, with improvements in erectile function, reduced germ cell apoptosis, and increased sperm maturation in animal models. However, clinical evidence remains limited. A small number of early-phase trials have reported preliminary safety findings and potential efficacy signals in PDE5i-nonresponsive ED and non-obstructive azoospermia; these findings are insufficient to establish validated safety or efficacy, and larger controlled trials are needed. Critical challenges remain: lack of standardized GMP protocols (inter-batch CV > 15%), incomplete long-term safety and biodistribution data, and no FDA/EMA approval for any regenerative therapy in this field as of 2026. Future directions include multi-omics (scRNA-seq, spatial omics), organoid platforms, synthetic sEVs, and AI-guided precision therapy based on genetic profiles (e.g., CYP19A1 rs10046). By integrating stem cell biology, exosome science, and nanotechnology, this review aims to provide a framework for developing next-generation precision nanomedicines for male reproductive health.