Exosomes in oncofertility: emerging roles in chemotherapy-induced reproductive damage and fertility preservation.
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ABSTRACT: Oncofertility has emerged as a critical interdisciplinary field addressing the reproductive challenges faced by cancer patients, particularly those undergoing chemotherapy. While chemotherapeutic agents remain indispensable in cancer therapy, their gonadotoxic effects frequently result in diminished ovarian reserve, impaired spermatogenesis, and long-term infertility. Exosomes - small extracellular vesicles enriched with nucleic acids, proteins, and lipids - are increasingly recognized as key mediators of intercellular communication in both pathological and regenerative contexts. Recent evidence suggests that chemotherapy alters exosome cargo, thereby amplifying cellular stress responses, oxidative damage, and bystander effects in gonadal tissues. Conversely, exosomes derived from mesenchymal stem cells, induced pluripotent stem cells (iPSCs), and other regenerative sources demonstrate the ability to restore ovarian and testicular function by reducing apoptosis, enhancing angiogenesis, and supporting germ cell survival. This dual role positions exosomes as both contributors to reproductive toxicity and promising therapeutic agents in fertility preservation strategies. However, clinical translation remains hindered by challenges including source heterogeneity, isolation methods, safety concerns, and regulatory barriers. This review highlights the emerging roles of exosomes in chemotherapy-induced reproductive damage, explores their regenerative potential, and outlines future directions for their integration into oncofertility practice. LAY SUMMARY: Cancer treatments such as chemotherapy save lives, but they often damage the ovaries and testes. This can lead to infertility in both women and men, which is one of the most difficult problems for cancer survivors. Finding ways to protect or restore fertility is, therefore, an important part of cancer care. Our work looks at very small particles called exosomes. These are natural messengers that carry proteins and genetic material between cells. We explain how chemotherapy changes these exosomes in a way that increases damage to reproductive organs. At the same time, we show that exosomes from stem cells may help repair this damage. In laboratory studies, they have been shown to protect eggs and sperm and reduce cell death of the reproductive organs during chemotherapy. Exosomes can also act as simple blood-based tests to detect damage and monitor recovery. This research is important because it points to new, less invasive ways to protect fertility during and after cancer treatment. If successful, exosome-based therapies could give patients not only a chance of survival but also the hope of having children in the future.