Heidi Mariadas 1, Jie-Hong Chen 2 and Kuo-Hu Chen 1,3,*
Abstract
Exosomes are nanoscale extracellular vesicles that mediate intercellular communication
by transporting microRNAs, proteins, and lipids. Generated through Endosomal Sorting
Complex Required for Transport (ESCRT)-dependent mechanisms or ESCRT-independent
pathways, exosomes are released when multivesicular bodies fuse with the plasma membrane. The ESCRT-dependent pathway involves sequential protein complexes (ESCRT-0,
I, II, III) that recognize and sort ubiquitinated cargo, induce membrane budding, and
facilitate vesicle scission. In contrast, the ESCRT-independent pathway relies on membrane
lipids such as ceramide and proteins like tetraspanins (CD9, CD63, CD81) to promote vesicle formation without ESCRT machinery. Furthermore, post-translational modifications,
including ubiquitination, sumoylation, and phosphorylation, further serve as molecular
switches, modulating the affinity of ESCRT complexes or cargo proteins for membrane
domains and affecting ILV formation rates. In reproductive medicine, exosomes regulate
oocyte maturation, embryo–endometrial crosstalk, placental development, and maternal–
fetal communication. Altered exosomal signaling contributes to obstetric complications,
including preeclampsia, gestational diabetes mellitus, and preterm birth, whereas distinct
exosomal miRNA signatures serve as potential diagnostic biomarkers. In gynecology,
dysregulated exosomes are implicated in endometriosis, polycystic ovary syndrome, premature ovarian insufficiency, and gynecological malignancies. In contrast, mesenchymal
stem cell-derived exosomes show therapeutic promise in restoring ovarian function and
enhancing fertility outcomes. The distinctive molecular profiles of circulating exosomes
enable minimally invasive diagnosis, while their biocompatibility and ability to cross biological barriers position them as vehicles for targeted drug delivery. Characterization
of accessible data provides non-invasive opportunities for disease monitoring. However,
clinical translation faces challenges, including standardization of isolation protocols, establishment of reference ranges for biomarkers, and optimization of therapeutic dosing. This
review summarizes exosome biogenesis, characterization methods, physiological functions,
and clinical applications in obstetrirics and gynecology, with an emphasis on their diagnostic
and therapeutic potential. Future directions include large-scale biomarker validation studies, engineering approaches to enhance exosome targeting, and integration with precision
medicine platforms to advance personalized reproductive healthcare.
- Method
This comprehensive review was conducted following the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to synthesize current knowledge on exosome molecular biology, cell physiology, and clinical applications in obstetrics and gynecology. The systematic review was registered in the public registration site OSF (registration number: 10.17605/OSF.IO/PVR8M at the website:
https://archive.org/details/osf-registrations-pvr8m-v1, accessed on 19 November 2025).
A systematic literature search was performed across multiple databases, including PubMed,
Ovid Medline, and Embase, up to October 2025, prioritizing recent publications from
the past five years while including seminal earlier studies for foundational concepts. A
flowchart of the literature review and paper retrieval is shown in Figure 1.