Multi-omic profiling of early pregnancy small and large plasma extracellular vesicles reveals placental, metabolic, and structural adaptation signatures

Abney, K.; Hollingsworth, T.; Schneider, A.; Brown, E. M.; Fazelinia, H.; Spruce, L.; Leite, R.; Parry, S.; Schwartz, N.; Conine, C. C.; Simmons, R.

doi:10.64898/2026.03.10.710888

bioRxiv · 10.64898/2026.03.10.710888

Multi-omic profiling of early pregnancy small and large plasma extracellular vesicles reveals placental, metabolic, and structural adaptation signatures

Abney, K.·Hollingsworth, T.·Schneider, A.·Brown, E. M.·Fazelinia, H.·Spruce, L.·Leite, R.·Parry, S.·Schwartz, N.·Conine, C. C.·Simmons, R.

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Abstract

Early human pregnancy is a critical period characterized by rapid growth and extensive maternal-fetal communication that influence maternal and fetal outcomes. Circulating extracellular vesicles (EVs) have the capacity to capture cargo that reflect these processes in real-time; however, signatures of EV subtypes during early pregnancy are poorly defined. Here we quantified mitochondrial DNA (mtDNA) and performed transcriptomic and proteomic profiling of small ([~]100 nm) and large ([~]200 nm) plasma EVs from n=10 normal pregnancies (11-15 weeks) to define subtype-specific molecular signatures. mtDNA and mitochondrial protein content were more abundant in large EVs (lEVs). lEVs also contained a more complex set of long RNAs enriched for placental, immune, and mitochondrial-related transcripts compared with small EVs (sEVs). Proteomic profiling showed enrichment of canonical EV markers and extracellular matrix proteins in sEVs, whereas lEVs were preferentially associated with pregnancy-specific proteins, including proteins related to placental hormone production. MicroRNAs (miRNAs) accounted for [~]25% of small RNAs in both EV subtypes with miR-223 and miR-16 enriched in lEVs and miR-639 enriched in sEVs. These data together, support a model where small and large plasma EVs have distinct, yet complementary signatures reporting systemic adaptations during the critical 11-15 week transition period. This work establishes a foundational framework for future studies linking EV signatures to placental dysfunction and adverse outcomes.

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Abney, K., Hollingsworth, T., Schneider, A., Brown, E. M., Fazelinia, H., Spruce, L., Leite, R., Parry, S., Schwartz, N., Conine, C. C., Simmons, R.. 2026-03-13. Multi-omic profiling of early pregnancy small and large plasma extracellular vesicles reveals placental, metabolic, and structural adaptation signatures. https://doi.org/10.64898/2026.03.10.710888

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