Placental Extracellular Vesicles in Preeclampsia: Molecular Cargo, Pathophysiological Roles, and Emerging Diagnostic and Therapeutic Frontiers

Abstract

Preeclampsia (PE) affects 2%–8% of pregnancies globally and remains a leading cause of maternal and perinatal mortality. A central clinical gap is the absence of analytically and clinically validated non‐invasive biomarkers capable of predicting PE before symptom onset. Current clinical tools, including angiogenic markers (sFlt‐1/PlGF ratio) and first‐trimester risk algorithms, have limitations that underscore the need for complementary approaches. Placental extracellular vesicles (EVs)—small particles released predominantly by syncytiotrophoblast cells—are implicated across PE pathophysiology. Circulating total small EV (sEV) concentrations, typically 30–150 nm and isolated by differential centrifugation or size‐exclusion chromatography, are measurably elevated in maternal circulation from the first trimester in women who develop PE; this operational, size‐ and isolation‐based definition does not by itself establish placental origin, which requires placental‐attribution markers (e.g., PLAP, syncytins) discussed in Section 2. Their molecular cargo, encompassing microRNAs (miR‐210, miR‐15a‐5p, miR‐520a‐5p, miR‐146a‐5p, miR‐93‐5p), anti‐angiogenic proteins (sFlt‐1, sEng), and hypoxia markers (HIF‐1α), reflects placental pathophysiology. Recent evidence has expanded the known pathophysiological reach of placental EVs: beyond endothelial dysfunction and angiogenic imbalance, they are now implicated in blood‐brain barrier disruption via claudin‐5 (CLDN5) downregulation, supporting a plausible mechanistic link to neurological complications of PE. Proteomic profiling of EV fractions identifies molecularly distinct PE subtypes, enabling investigational subtype discrimination beyond current clinical criteria. Recent in vivo proof‐of‐concept evidence in a rat model demonstrates that amniotic fluid‐derived EV‐associated miR‐146a‐5p ameliorates PE phenotypes, opening a preclinical therapeutic avenue. This narrative review synthesises evidence from a structured PubMed/MEDLINE and Scopus search covering 2017–March 2025 on placental EV biogenesis, cargo heterogeneity, immune modulation, organ‐specific pathological consequences, and translational potential as first‐trimester liquid biopsy candidates. Methodological standardization challenges and future research priorities are discussed.