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

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.