Strategies and Challenges of Mesenchymal Stem Cells-Derived Extracellular Vesicles in Infertility

Having genetically related offspring remains an unattainable dream for couples with reproductive failure. Mesenchymal stem cells (MSCs) are multipotent stromal cells derived from various human tissues and organs. As critical paracrine effectors of MSCs, extracellular vesicles (EVs) can carry and deliver bioactive content, thereby participating in intercellular communication and determining cell fate. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promising therapeutic effects, including repairing injured endometria, restoration of ovarian functions, and improving sperm quantity, morphology, and motility, owing to their regenerative potential, abundant sources, high proliferation rates, low immunogenicity, and lack of ethical issues. However, limited knowledge on purification and isolation of MSC-EVs, therapeutic effects, and unpredictable safety have caused challenges in overcoming female and male infertility. To overcome them, future studies should focus on modification/engineering of MSC-EVs with therapeutic biomolecules and combining attractive biomaterials and MSC-EVs. This review highlights the latest studies on MSC-EVs therapies in infertility and the major challenges that must be overcome before clinical translation. Impact statement Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) represent a novel and promising therapeutic approach in infertility, owing to their regenerative potential, abundant sources, high proliferation rates, low immunogenicity, and lack of ethical issues. Promising therapeutic effects include repairing injured endometria, restoring ovarian functions, and improving sperm quantity, morphology, and motility. However, research on MSC-EVs therapies (MSC-EV-Ts) in infertility still needs improvement in many aspects, including establishing standard disease models, optimizing administration routes, and using tissue engineering to enhance retention and efficacy. This review highlights the latest studies on the potential mechanisms and preclinical effects of MSC-EV-Ts, and provides suggestions for future studies.