Extracellular Vesicle-Associated Non-Coding RNAs in Preeclampsia: Mechanistic Insights, Biomarker Discovery, and Emerging Nanomedicine Concepts.

Preeclampsia (PE) is a complex multisystem disorder that affects 2-8% of pregnancies worldwide and poses substantial risks to maternal and fetal health. Current diagnostic approaches rely largely on clinical signs and angiogenic biomarkers, and available treatments remain primarily supportive; they do not directly reverse the placental or systemic mechanisms that drive the disease. Extracellular vesicles (EVs), including small EVs often termed exosomes, carry non-coding RNAs (ncRNAs) that may contribute to placental-maternal communication in both normal and pathological pregnancy. In PE, altered EV-associated microRNAs, long non-coding RNAs, and circular RNAs have been detected in placental tissues, trophoblast-derived systems, maternal plasma or serum, urine, amniotic fluid, and other pregnancy-related samples. However, these matrices should not be assumed to indicate definitive tissue or cellular origins without appropriate source-attribution methods. This review summarizes current evidence on EV-associated ncRNAs in PE from three perspectives: mechanistic studies, biomarker discovery, and exploratory nanomedicine strategies. First, we discuss how dysregulated EV-associated ncRNAs may contribute to trophoblast dysfunction, immune-inflammatory imbalance, endothelial injury, and angiogenic dysregulation. Second, we evaluate EV-associated ncRNAs as candidate liquid-biopsy biomarkers, emphasizing that most reported signatures remain at the discovery or early validation stage. Their clinical implementation will require standardized EV isolation, RNA profiling, normalization procedures, and validation in independent longitudinal cohorts. Third, we discuss engineered EVs and EV-mimetic nanocarriers as experimental platforms for ncRNA delivery and distinguish these preclinical therapeutic concepts from clinically established PE management. Rather than suggesting immediate diagnostic or therapeutic readiness, this review highlights the opportunities and limitations of EV-associated ncRNAs as a framework for future PE research. Key challenges include EV heterogeneity, limited discrimination among vesicular subtypes, uncertain tissue origins of circulating EV cargo, poor reproducibility across cohorts, safety concerns during pregnancy, scalable manufacturing, and ethical considerations related to maternal-fetal interventions. Future studies integrating rigorously characterized EV populations, multi-omics profiling, functional validation, and longitudinal clinical sampling are essential to determine whether EV-associated ncRNAs can be translated into reliable PE biomarkers or safe nanomedicine-based interventions.