Placenta-Derived Extracellular Vesicles (pdEVs): Key Mediators That Affect the Metabolic Health of Offspring in Early Nutritional Environments

Placenta-derived extracellular vesicles (EVs), particularly exosomes, serve as key mediators that influence metabolic programming in offspring under adverse early nutritional conditions, such as maternal obesity or gestational diabetes. They respond to maternal nutritional disturbances-such as obesity or gestational diabetes-by altering the composition of the miRNAs and proteins they carry. Evidence from in vivo and in vitro studies suggests that these modified EVs influence offspring metabolic programming through multiple putative pathways: regulating fetal pancreatic β-cell development and function, modulating lipogenesis via PPARγ signaling, affecting placental angiogenesis, and promoting inflammation and epigenetic alterations. By transmitting maternal environmental signals to the fetus, placental EVs are hypothesized to contribute to long-term metabolic phenotypes and disease susceptibility. This review critically examines the current evidence positioning placental EVs as key messengers in maternal-fetal communication, evaluates the strength of evidence supporting their role in shaping offspring metabolic health, identifies major knowledge gaps (e.g., limited direct evidence in human offspring, lack of standardized isolation methods), and suggests their potential as early intervention biomarkers or therapeutic targets for preventing metabolic disorders in offspring. We also highlight the need for prospective cohort studies and mechanistic validation in appropriate animal models to establish causality.