The Role of Exosomal miRNAs in Female Infertility: Therapeutic Potential and Mechanisms of Action

Reproductive disorders, including preeclampsia (PE), endometriosis, premature ovarian failure (POF), and polycystic ovary syndrome (PCOS), present substantial challenges to women’s reproductive health. Exosomes (EXOs) are cell-derived vesicles containing molecules that influence target cells’ gene expression and cellular behavior. Among their cargo, microRNAs (miRNAs)—short, non-coding RNAs typically 19–25 nucleotides in length—play a crucial role in post-transcriptional gene regulation and have been extensively studied for their therapeutic potential. miRNAs are considered therapeutic targets because they regulate key cellular pathways such as proliferation, apoptosis, angiogenesis, and tissue repair. This review examines the role of exosomal miRNAs from sources such as mesenchymal stem cells (MSCs), plasma, and amniotic fluid in female reproductive disorders, including PE, POF, PCOS, and endometriosis. We discuss their biological origins, mechanisms of miRNA sorting and packaging, and their therapeutic applications in modulating disease progression. By categorizing miRNAs according to their beneficial or detrimental effects in specific conditions, we aim to simplify the understanding of their roles in female infertility. Graphical Abstract Similar content being viewed by others Data Availability No datasets were generated or analyzed during the current study.

Kicińska, A. M. (2023). Immunological and metabolic causes of infertility in polycystic ovary syndrome. Biomedicines, 11(6), 1567. Ahmadi, H. (2023). Long-Term effects of ART on the health of the offspring. International Journal of Molecular Sciences, 24(17), 13564. Fauque, P., et al. (2020). Reproductive technologies, female infertility, and the risk of imprinting-related disorders. Clinical Epigenetics, 12(1), 191. Bhartiya, D., et al. (2022). Very small embryonic-like stem cells (VSELs) regenerate whereas mesenchymal stromal cells (MSCs) rejuvenate diseased reproductive tissues. Stem Cell Reviews and Reports, 18(5), 1718–1727. van Niel, G., D’Angelo, G., & Raposo, G. (2018). Shedding light on the cell biology of extracellular vesicles. Nature Reviews Molecular Cell Biology, 19(4), 213–228. Jiang, X., et al. (2024). Engineered exosomes loaded with triptolide: An innovative approach to enhance therapeutic efficacy in rheumatoid arthritis. International Immunopharmacology, 129, 111677. McAndrews, K. M., & Kalluri, R. (2019). Mechanisms associated with biogenesis of exosomes in cancer. Molecular Cancer, 18(1), 52. Araldi, R. P. (2020). Stem Cell-Derived exosomes as therapeutic approach for neurodegenerative disorders: From biology to biotechnology. Cells, 9(12), 2663. Eldaly, A. S., et al. (2022). Systemic anti-inflammatory effects of mesenchymal stem cells in burn: A systematic review of animal studies. Journal of Clinical and Translational Research, 8(4), 276–291. Pegtel, D. M., & Gould, S. J. (2019). Exosomes. Annual Review of Biochemistry, 88, 487–514. Zhang, B. (2021). Topical application of mesenchymal stem cell exosomes alleviates the imiquimod induced Psoriasis-Like inflammation. International Journal of Molecular Sciences, 22(2). Saadh, M. J., et al. (2024). Dual role of mesenchymal stem/stromal cells and their cell-free extracellular vesicles in colorectal cancer. Cell Biochemistry and Function, 42(2), e3962. Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116(2), 281–297. Png, K. J., et al. (2011). A MicroRNA Regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature, 481(7380), 190–194. Gee, H. E. (2008). MicroRNA-10b and breast cancer metastasis. Nature, 455(7216): p. E8-9; author reply E9. Tay, Y., et al. (2008). MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature, 455(7216), 1124–1128. Kota, J., et al. (2009). Therapeutic MicroRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell, 137(6), 1005–1017. Ma, L., Teruya-Feldstein, J., & Weinberg, R. A. (2007). Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature, 449(7163), 682–688. Chavda, V. P., et al. (2023). Exosome nanovesicles: A potential carrier for therapeutic delivery. Nano Today, 49, 101771. Barile, L., et al. (2017). Roles of exosomes in cardioprotection. European Heart Journal, 38(18), 1372–1379. Ghorbani, F., et al. (2022). Renoprotective effects of extracellular vesicles: A systematic review. Gene Reports, 26, 101491. Widjaja, G., et al. (2022). Mesenchymal stromal/stem cells and their exosomes application in the treatment of intervertebral disc disease: A promising frontier. International Immunopharmacology, 105, 108537. Patel, A. A., et al. (2024). Application of mesenchymal stem cells derived from the umbilical cord or Wharton’s jelly and their extracellular vesicles in the treatment of various diseases. Tissue and Cell, 89, 102415. Jiang, X., Wu, S., & Hu, C. (2023). A narrative review of the role of exosomes and caveolin-1 in liver diseases and cancer. International Immunopharmacology, 120, 110284. Gurung, S., et al. (2021). The exosome journey: From biogenesis to uptake and intracellular signalling. Cell Communication and Signaling, 19(1), 47. Alia Moosavian, S., et al. (2022). Melanoma-derived exosomes: Versatile extracellular vesicles for diagnosis, metastasis, immune modulation, and treatment of melanoma. International Immunopharmacology, 113, 109320. Wollert, T., & Hurley, J. H. (2010). Molecular mechanism of multivesicular body biogenesis by ESCRT complexes. Nature, 464(7290), 864–869. Ortiz, G. G. R., et al. (2023). The developing role of extracellular vesicles in autoimmune diseases: Special attention to mesenchymal stem cell-derived extracellular vesicles. International Immunopharmacology, 122, 110531. van der Pol, E., et al. (2012). Classification, functions, and clinical relevance of extracellular vesicles. Pharmacological Reviews, 64(3), 676–705. Segura, E., et al. (2007). CD8 + dendritic cells use LFA-1 to capture MHC-peptide complexes from exosomes in vivo. The Journal of Immunology, 179(3), 1489–1496. Mulcahy, L. A., Pink, R. C., & Carter, D. R. (2014). Routes and mechanisms of extracellular vesicle uptake. Journal of Extracellular Vesicles, 3. McKelvey, K. J., et al. (2015). Exosomes: Mechanisms of uptake. Journal of Circulating Biomarkers, 4, 7–7. Moshkanbaryans, L., Chan, L. S., & Graham, M. E. (2014). The biochemical properties and functions of CALM and AP180 in clathrin mediated endocytosis. Membranes, 4(3), 388–413. Subra, C., et al. (2010). Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. Journal of Lipid Research, 51(8), 2105–2120. Koga, Y., et al. (2011). Exosome can prevent RNase from degrading MicroRNA in feces. Journal of Gastrointestinal Oncology, 2(4), 215–222. Andreu, Z., & Yáñez-Mó, M. (2014). Tetraspanins in extracellular vesicle formation and function. Frontiers in Immunology, 5, 442. Yu, M. Y., et al. (2023). Exosomal miRNAs-mediated macrophage polarization and its potential clinical application. International Immunopharmacology, 117, 109905. Kalluri, R., & LeBleu, V. S. (2020). The biology, function, and biomedical applications of exosomes. Science, 367(6478), eaau6977. Zheng, X. L. (2023). Exosomal miR-127-5p from BMSCs alleviated sepsis-related acute lung injury by inhibiting neutrophil extracellular trap formation. International Immunopharmacology, 123, 110759. Li, X., & Yang, N. (2023). Exosome miR-223-3p in the bone marrow-derived mesenchymal stem cells alleviates the inflammation and airway remodeling through NLRP3-induced ASC/Caspase-1/GSDMD signaling pathway. International Immunopharmacology, 123, 110746. Goldie, B. J., et al. (2014). Activity-associated MiRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Research, 42(14), 9195–9208. Valadi, H., et al. (2007). Exosome-mediated transfer of mRNAs and MicroRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology, 9(6), 654–659. Kogure, T., et al. (2011). Intercellular nanovesicle-mediated MicroRNA transfer: A mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology, 54(4), 1237–1248. Chiba, M., Kimura, M., & Asari, S. (2012). Exosomes secreted from human colorectal cancer cell lines contain mRNAs, MicroRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines. Oncology Reports, 28(5), 1551–1558. Montecalvo, A., et al. (2012). Mechanism of transfer of functional MicroRNAs between mouse dendritic cells via exosomes. Blood, 119(3), 756–766. Zhou, W., et al. (2014). Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell, 25(4), 501–515. van Balkom, B. W., et al. (2013). Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. Blood, 121(19), 3997–4006. Zhao, Y., Jin, L. J., & Zhang, X. Y. (2021). Exosomal miRNA-205 promotes breast cancer chemoresistance and tumorigenesis through E2F1. Aging (Albany NY), 13(14), 18498–18514. Fabbri, M., et al. (2012). MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A, 109(31), E2110–E2116. Qu, Q., et al. (2022). miR-126-3p containing exosomes derived from human umbilical cord mesenchymal stem cells promote angiogenesis and attenuate ovarian granulosa cell apoptosis in a preclinical rat model of premature ovarian failure. Stem Cell Research & Therapy, 13(1), 352. Sun, B., et al. (2019). miR-644-5p carried by bone mesenchymal stem cell-derived exosomes targets regulation of p53 to inhibit ovarian granulosa cell apoptosis. Stem Cell Research & Therapy, 10(1), 360. Xiao, G. Y., et al. (2016). Exosomal miR-10a derived from amniotic fluid stem cells preserves ovarian follicles after chemotherapy. Scientific Reports, 6, 23120. Gao, T., et al. (2023). MicroRNA-22-3p in human umbilical cord mesenchymal stem cell-secreted exosomes inhibits granulosa cell apoptosis by targeting KLF6 and ATF4-ATF3-CHOP pathway in POF mice. Apoptosis, 28(7–8), 997–1011. Cai, J. H., Sun, Y. T., & Bao, S. (2022). HucMSCs-exosomes containing miR-21 promoted Estrogen production in ovarian granulosa cells via LATS1-mediated phosphorylation of LOXL2 and YAP. General and Comparative Endocrinology, 321-322, 114015. Geng, Z. (2022). Human Amniotic Fluid Mesenchymal Stem Cell-Derived Exosomes Inhibit Apoptosis in Ovarian Granulosa Cell via miR-369-3p/YAF2/PDCD5/p53 Pathway. Oxidative Medicine and Cellular Longevity, 2022, 3695848. Yang, M., et al. (2020). Bone marrow mesenchymal stem cell-derived Exosomal miR-144-5p improves rat ovarian function after chemotherapy-induced ovarian failure by targeting PTEN. Laboratory Investigation, 100(3), 342–352. Salehi, R. (2023). Granulosa cell-derived miR-379-5p regulates macrophage polarization in polycystic ovarian syndrome. Frontiers in Immunology, 14, 1104550. Salehi, R., et al. (2023). Androgen-induced Exosomal miR-379-5p release determines granulosa cell fate: Cellular mechanism involved in polycystic ovaries. Journal of Ovarian Research, 16(1), 74. Yuan, D., et al. (2021). PCOS follicular fluid derived Exosomal miR-424-5p induces granulosa cells senescence by targeting CDCA4 expression. Cellular Signalling, 85, 110030. Zhao, Y., et al. (2019). Mesenchymal stem cells derived Exosomal miR-323-3p promotes proliferation and inhibits apoptosis of cumulus cells in polycystic ovary syndrome (PCOS). Artificial Cells, Nanomedicine, and Biotechnology, 47(1), 3804–3813. Zhao, Y., et al. (2022). Exosomal miR-143-3p derived from follicular fluid promotes granulosa cell apoptosis by targeting BMPR1A in polycystic ovary syndrome. Scientific Reports, 12(1), 4359. Hu, J., et al. (2023). Adipocyte-derived Exosomal miR-30c-5p promotes ovarian angiogenesis in polycystic ovary syndrome via the SOCS3/STAT3/VEGFA pathway. Journal of Steroid Biochemistry and Molecular Biology, 230, 106278. Zhou, Z., et al. (2022). Follicular Fluid-Derived Exosomal MicroRNA-18b-5p regulates PTEN-Mediated PI3K/Akt/mTOR signaling pathway to inhibit polycystic ovary syndrome development. Molecular Neurobiology, 59(4), 2520–2531. Wang, M., et al. (2023). Follicular fluid derived Exosomal miR-4449 regulates cell proliferation and oxidative stress by targeting KEAP1 in human granulosa cell lines KGN and COV434. Experimental Cell Research, 430(2), 113735. Zhang, Y., et al. (2021). Down-regulation of Exosomal miR-214-3p targeting CCN2 contributes to endometriosis fibrosis and the role of exosomes in the horizontal transfer of miR-214-3. Reproductive Sciences, 28(3), 715–727. Huang, Y., et al. (2022). Endometriosis derived Exosomal miR-301a-3p mediates macrophage polarization via regulating PTEN-PI3K axis. Biomedicine & Pharmacotherapy, 147, 112680. Ji, J., et al. (2024). Exosomes from ectopic endometrial stromal cells promote M2 macrophage polarization by delivering miR-146a-5p. International Immunopharmacology, 128, 111573. Jiang, Y. (2022). Exosomes from the uterine cavity mediate immune dysregulation via inhibiting the JNK signal pathway in endometriosis. Biomedicines, 10(12), 3110. Wu, D., et al. (2018). Exosomal miR-214 from endometrial stromal cells inhibits endometriosis fibrosis. Molecular Human Reproduction, 24(7), 357–365. Zhang, L., et al. (2020). Exosomal miR-22-3p derived from peritoneal macrophages enhances proliferation, migration, and invasion of ectopic endometrial stromal cells through regulation of the SIRT1/NF-κB signaling pathway. European Review for Medical and Pharmacological Sciences, 24(2), 571–580. Zhang, M., et al. (2022). Endometrial epithelial cells-derived exosomes deliver microRNA-30c to block the BCL9/Wnt/CD44 signaling and inhibit cell invasion and migration in ovarian endometriosis. Cell Death Discovery, 8(1), 151. Xueya, Z., et al. (2020). Exosomal encapsulation of miR-125a-5p inhibited trophoblast cell migration and proliferation by regulating the expression of VEGFA in preeclampsia. Biochemical and Biophysical Research Communications, 525(3), 646–653. Liu, H., et al. (2020). Exosomal microRNA-139-5p from mesenchymal stem cells accelerates trophoblast cell invasion and migration by motivation of the ERK/MMP-2 pathway via downregulation of protein tyrosine phosphatase. The Journal of Obstetrics and Gynaecology Research, 46(12), 2561–2572. Sun, J., & Zhang, W. (2024). Huc-MSC-derived Exosomal miR-144 alleviates inflammation in LPS-induced preeclampsia-like pregnant rats via the FosB/Flt-1 pathway. Heliyon, 10(2), e24575. Wang, Y., & Chen, A. (2022). Mast cell-derived Exosomal miR-181a-5p modulated trophoblast cell viability, migration, and invasion via YY1/MMP-9 axis. Journal of Clinical Laboratory Analysis, 36(7), e24549. Schoemaker, J., Drexhage, H., & Hoek, A. (1997). Premature ovarian failure and ovarian autoimmunity. Endocrine Reviews, 18(1), 107–134. Fu, Y. X., et al. (2021). Human mesenchymal stem cell treatment of premature ovarian failure: New challenges and opportunities. Stem Cell Research & Therapy, 12(1), 161. Kenney, L. B., et al. (2001). High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer, 91(3), 613–621. Orlandini, C., et al. (2015). Genes involved in the pathogenesis of premature ovarian insufficiency. Minerva Ginecologica, 67(5), 421–430. Chapman, C., Cree, L., & Shelling, A. N. (2015). The genetics of premature ovarian failure: Current perspectives. International Journal of Women's Health, 7, 799–810. Ayesha, V. Jha, and D. Goswami (2016) Premature Ovarian Failure: An Association with Autoimmune Diseases. Journal of Clinical and Diagnostic Research, 10(10):Qc10-qc12. Sassarini, J., Lumsden, M. A., & Critchley, H. O. (2015). Sex hormone replacement in ovarian failure - new treatment concepts. Best Practice & Research Clinical Endocrinology & Metabolism, 29(1), 105–114. Ebrahimi, M., Akbari, F., & Asbagh (2011). Pathogenesis And causes of premature ovarian failure: An update. International Journal of Fertility and Sterility, 5(2), 54–65. Mousavi-Jarrrahi, S. H., et al. (2013). Addressing the younger age at onset in breast cancer patients in Asia: An age-period-cohort Analysis of Fifty years of quality data from the international agency for research on cancer. ISRN Oncology, 2013, 429862. Gradishar, W. J., & Schilsky, R. L. (1988). Effects of cancer treatment on the reproductive system. Critical Reviews in Oncology Hematology, 8(2), 153–171. Santoro, N. (2003). Mechanisms of premature ovarian failure. Annales d'endocrinologie (Paris), 64(2), 87–92. Akogullari, D., & Uluer, E. T., Vatansever, H. S. (2018) Investigation of the Relation between Follicular Atresia and Granulosa Cells in Terms of Cell Death Mechanisms in Premature Ovarian Failure Model. Proceedings, 2. https://doi.org/10.3390/proceedings2251529 Happo, L., et al. (2010). Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim. Blood, 116(24), 5256–5267. Chesler, L., et al. (2008). Chemotherapy-induced apoptosis in a Transgenic model of neuroblastoma proceeds through p53 induction. Neoplasia (New York, N.Y.), 10(11), 1268–1274. Sandhu, R., et al. (2014). Overexpression of miR-146a in basal-like breast cancer cells confers enhanced tumorigenic potential in association with altered p53 status. Carcinogenesis, 35(11), 2567–2575. Ho, J., et al. (2011). The pro-apoptotic protein Bim is a MicroRNA target in kidney progenitors. Journal of the American Society of Nephrology, 22(6), 1053–1063. Luo, H., et al. (2019). Identification of MicroRNAs in granulosa cells from patients with different levels of ovarian reserve function and the potential regulatory function of miR-23a in granulosa cell apoptosis. Gene, 686, 250–260. Rocha, A. L. (2019). Recent advances in the Understanding and management of polycystic ovary syndrome. F1000Res, 8, 565. Norman, R. J., et al. (2007). Polycystic ovary syndrome. Lancet, 370(9588), 685–697. Cao, M., et al. (2022). Adipose mesenchymal stem cell-derived Exosomal MicroRNAs ameliorate polycystic ovary syndrome by protecting against metabolic disturbances. Biomaterials, 288, 121739. Xiong, Y., et al. (2011). Low-grade chronic inflammation in the peripheral blood and ovaries of women with polycystic ovarian syndrome. European Journal of Obstetrics & Gynecology and Reproductive Biology, 159(1), 148–150. Lv, Y., et al., (2025) Decreased miR-128-3p in serum exosomes from polycystic ovary syndrome induces ferroptosis in granulosa cells via the p38/JNK/SLC7A11 axis through targeting CSF1. Cell Death Discovery, 11(1):64. Wang, M., et al. (2017). MicroRNA-27a-3p affects estradiol and androgen imbalance by targeting Creb1 in the granulosa cells in mouse polycytic ovary syndrome model. Reproductive Biology, 17(4), 295–304. Cui, M., et al. (2024). CRISPR-based dissection of microRNA-23a ~ 27a ~ 24– 2 cluster functionality in hepatocellular carcinoma. Oncogene, 43(36), 2708–2721. Zubrzycka, A. (2020). Genetic, epigenetic, and steroidogenic modulation mechanisms in endometriosis. Journal of Clinical Medicine, 9(5), 1309. Zondervan, K. T. (2018). Endometriosis. Nature Reviews Disease Primers, 4(1), 9. Giudice, L.C., & L. C. Kao (2004) Endometriosis.Lancet, 364(9447):1789-99. Da Broi, M. G., & Navarro, P. A. (2016). Oxidative stress and oocyte quality: Ethiopathogenic mechanisms of minimal/mild endometriosis-related infertility. Cell and Tissue Research, 364(1), 1–7. Sun, L., et al. (2024). Exosomal miR-21-5p derived from endometrial stromal cells promotes angiogenesis by targeting TIMP3 in ovarian endometrial cysts. Journal of Molecular Medicine (Berl), 102(11), 1327–1342. Peng, Y., et al. (2018). Upregulation of S100A6 in patients with endometriosis and its role in ectopic endometrial stromal cells. Gynecological Endocrinology, 34(9), 815–820. Bacci, M., et al. (2009). Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease. The American Journal of Pathology, 175(2), 547–556. Matsubara, K. (2021). Pathophysiology of preeclampsia: The role of exosomes. International Journal of Molecular Sciences, 22(5), 547–565. Jiang, Y., et al. (2022). microRNA-140-5p from human umbilical cord mesenchymal stem cells-released exosomes suppresses preeclampsia development. Functional and Integrative Genomics, 22(5), 813–824. Wang, D., et al. (2020). Human umbilical cord mesenchymal stem cell-derived exosome-mediated transfer of microRNA-133b boosts trophoblast cell proliferation, migration and invasion in preeclampsia by restricting SGK1. Cell Cycle, 19(15), 1869–1883. Lu, J., et al. (2022). Small RNA sequencing reveals placenta-derived Exosomal MicroRNAs associated with preeclampsia. Journal of Hypertension, 40(5), 1030–1041. Li, Y. (2024). Exosomal encapsulation of miR-3198 promotes proliferation and migration of trophoblasts in preeclampsia. Journal of Assisted Reproduction and Genetics, 40(5), 1030–1041. Chen, Y., et al. (2023). Exosomal microRNA-342-5p from human umbilical cord mesenchymal stem cells inhibits preeclampsia in rats. Functional and Integrative Genomics, 23(1), 27. Wang, Z., et al. (2019). MiRNA-548c-5p downregulates inflammatory response in preeclampsia via targeting PTPRO. Journal of Cellular Physiology, 234(7), 11149–11155. Zhou, C., et al. (2022). Exosomal miR-195 in hUC-MSCs alleviates hypoxia-induced damage of trophoblast cells through tissue factor pathway inhibitor 2. Current Research in Translational Medicine, 70(4), 103352. Chen, Z., et al. (2022). Plasma Exosomal miR-199a-5p derived from preeclampsia with severe features impairs endothelial cell function via targeting SIRT1. Reproductive Sciences, 29(12), 3413–3424. Sun, B., et al. (2023). MiR-135b-5p targets ADAM12 to suppress invasion and accelerate trophoblast apoptosis in preeclampsia. Placenta, 143, 69–79. Wu, D., et al. (2024). Trophoblast cell-derived extracellular vesicles regulate the polarization of decidual macrophages by carrying miR-141-3p in the pathogenesis of preeclampsia. Scientific Reports, 14(1), 24529. Ratti, M., et al. (2020). MicroRNAs (miRNAs) and long Non-Coding RNAs (lncRNAs) as new tools for cancer therapy: First steps from bench to bedside. Targeted Oncology, 15(3), 261–278. O’Brien, J., et al. (2018). Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Frontiers in Endocrinology, 2018, 9 Tian, Y., et al. (2014). A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials, 35(7), 2383–2390. Nagelkerke, A., et al. (2021). Extracellular vesicles for tissue repair and regeneration: Evidence, challenges and opportunities. Advanced Drug Delivery Reviews, 175, 113775. Robbins, P. D., & Morelli, A. E. (2014). Regulation of immune responses by extracellular vesicles. Nature Reviews Immunology, 14(3), 195–208. Watson, D. C., et al. (2016). Efficient production and enhanced tumor delivery of engineered extracellular vesicles. Biomaterials, 105, 195–205. Yerneni, S. S., et al. (2019). Rapid On-Demand extracellular vesicle augmentation with versatile oligonucleotide tethers. Acs Nano, 13(9), 10555–10565. Sato, Y. T., et al. (2016). Engineering hybrid exosomes by membrane fusion with liposomes. Scientific Reports, 6(1), 21933. Kooijmans, S. A. A., et al. (2016). PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. Journal of Controlled Release, 224, 77–85. Ranjan, P., et al. (2023). Challenges and future scope of exosomes in the treatment of cardiovascular diseases. Journal of Physiology, 601(22), 4873–4893. Lener, T., et al. (2015). Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. Journal of Extracellular Vesicles, 4, 30087. Takakura, Y., et al. (2024). Quality and safety considerations for therapeutic products based on extracellular vesicles. Pharmaceutical Research, 41(8), 1573–1594. Zhu, L., et al. (2020). Isolation and characterization of exosomes for cancer research. Journal of Hematology & Oncology, 13(1), 152. Lin, S., et al. (2020). Progress in Microfluidics-Based exosome separation and detection technologies for diagnostic applications. Small (Weinheim an Der Bergstrasse, Germany), 16(9), e1903916. Ding, L., et al. (2021). A holistic review of the State-of-the-Art microfluidics for exosome separation: An overview of the current status, existing obstacles, and future outlook. Small (Weinheim an Der Bergstrasse, Germany), 17(29), e2007174. Kamerkar, S., et al. (2017). Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature, 546(7659), 498–503. Coumans, F. A. W., et al. (2017). Methodological guidelines to study extracellular vesicles. Circulation Research, 120(10), 1632–1648. Mohammadi, M., et al. (2021). Emerging technologies and commercial products in exosome-based cancer diagnosis and prognosis. Biosensors & Bioelectronics, 183, 113176. Théry, C. (2006). Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Current Protocols in Cell Biology, 2006. Chapter 3: p. Unit 3.22. Sidhom, K., Obi, P. O., & Saleem, A. (2020). A review of Exosomal isolation methods: Is size exclusion chromatography the best option??. International Journal of Molecular Sciences, 21(18), Chapter 3, Unit 3.22. Royo, F. (2016). Comparative MiRNA analysis of urine extracellular vesicles isolated through five different methods. Cancers (Basel), 8(12), 6466. Andreu, Z., et al. (2016). Comparative analysis of EV isolation procedures for MiRNAs detection in serum samples. Journal of Extracellular Vesicles, 5, 31655. Van Deun, J. (2014). The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling. Journal of Extracellular Vesicles, 3(1), 24858. Lobb, R. J., et al. (2015). Optimized exosome isolation protocol for cell culture supernatant and human plasma. Journal of Extracellular Vesicles, 4, 27031. Contreras-Naranjo, J. C., Wu, H. J., & Ugaz, V. M. (2017). Microfluidics for exosome isolation and analysis: Enabling liquid biopsy for personalized medicine. Lab on A Chip, 17(21), 3558–3577. Rekker, K., et al. (2014). Comparison of serum exosome isolation methods for MicroRNA profiling. Clinical Biochemistry, 47(1–2), 135–138. Taylor, D. D., Zacharias, W., & Gercel-Taylor, C. (2011). Exosome isolation for proteomic analyses and RNA profiling. Methods in Molecular Biology, 728, 235–246.

The authors are thankful to the Deanship of Research and Graduate Studies, King Khalid University, Abha, Saudi Arabia, for financially supporting this work through the Large Research Group Project under Grant No. R.G.P.2/517/45. Author information Authors and Affiliations Contributions Waleed Al Abdulmonem, Marya Ahsan, Asma’a H. Mohamed, and Ayaz Khurram Mallick collected the information, wrote the manuscript, and designed the figures. Alaa Shafie and Hassan Swed Alzahrani contributed to collection of information, co-wrote, and critically revised the manuscript. Hatim T.O. Ali and Amal Adnan Ashour critically revised the manuscript. Mohammed Tarek Mirdad critically revised the manuscript and codesigned the figures. Safia Obaidur Rab and Hisham Ali Waggiallah critically revised the manuscript. All authors contributed to the article and approved the submitted version. Corresponding author Ethics declarations Ethics Approval and Consent to Participate Not applicable. Consent for Publication Not applicable. Competing Interests The authors declare no competing interests. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Abdulmonem, W.A., Ahsan, M., Mallick, A.K. et al. The Role of Exosomal miRNAs in Female Infertility: Therapeutic Potential and Mechanisms of Action. Stem Cell Rev and Rep 21, 1141–1159 (2025). https://doi.org/10.1007/s12015-025-10869-w Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s12015-025-10869-w