Extracellular Vesicles From Human Fallopian Tubes Enhance IVF Embryo Development and Contain Functional Proteins Including YWHAZ.

Extracellular vesicles (EVs) in the mammalian oviduct constitute a key maternal regulatory system that maintains redox balance during early embryogenesis, yet their molecular cargo and functional relevance in human embryos remain poorly defined. Here, we show that human Fallopian tube-derived EVs (oEVs) are rapidly internalized by human preimplantation embryos and improve developmental quality in vitro, increasing high-quality Day 3 embryo formation and blastocyst development. Label-free proteomics identified 6505 oEV proteins, with metabolic, antioxidant and stress-response pathways strongly enriched. Cross-reference with four independent datasets revealed a conserved protein subset shared across secretory-phase oviduct fluid, pluripotent stem cell-derived EVs and in-vivo-developed embryos; among these, YWHAZ was prioritized for functional validation because of its abundance in oEVs, its presence across embryo-related datasets, and its known involvement in stress-response pathways. We found that Ywhaz-deficient mouse embryos exhibit elevated oxidative and apoptotic stress, transcriptional signatures of impaired glutathione metabolism, and failure to survive to birth despite normal blastocyst morphology. Recombinant YWHAZ protein alone failed to enter intact embryos, whereas engineered YWHAZ-loaded EVs were efficiently internalized and significantly reduced intracellular ROS and apoptosis, restoring redox status towards in vivo levels without compromising implantation or foetal growth. Taken together, these findings identify YWHAZ protein as a conserved vesicle-delivered regulator of redox homeostasis and demonstrate that EV-mediated molecular delivery can partially rescue the oxidative stress burden characteristic of in vitro embryo culture. This work provides mechanistic insight into the maternal redox support system of the oviduct and establishes a foundation for EV-based engineering of next-generation embryo culture strategies. Fallopian tube extracellular vesicles enhance human IVF embryo development by delivering functional proteins such as YWHAZ to regulate oxidative stress and blastocyst formation. Large Scale Data Proteomic data are available in the PRIDE database under accession number PXD054946 (https://www.ebi.ac.uk/pride/). Ywhaz-KO embryo RNA-sequencing data are available in the GEO database under accession number GSE294735 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294735.