Epididymosomes: a key to sperm maturation and infertility therapeutics.

Epididymosomes as key communication mediators for maintaining organismal homeostasis and coordinating life activities, play a crucial role in the reproductive system. Epididymosomes directly drive sperm to complete functional maturation in the epididymis by delivering bioactive molecules such as proteins, nucleic acids, and lipids, endowing them with motility and fertilization potential. Yet, deviations in epididymosome quantity, compositional profiles, or functional capacities may impede sperm maturation and culminate in fertilization failure, thereby establishing them as key etiological contributors to male infertility. This review comprehensively synthesizes the core roles of epididymosomes in sperm functional maturation, detailing their mechanisms of biogenesis, molecular makeup, and the molecular networks and signaling pathways that govern sperm maturation. It also focuses on exploring the prospects for clinical application of epididymosomes in treating male infertility, alongside the current limitations that need to be addressed. We put forward the development of novel diagnostic markers and targeted therapeutic strategies, drawing on how epididymosome contents regulate sperm functional maturation, and offer actionable suggestions for future research.