Targeted delivery of RGD-JEG-3-EVs for placental vascular regeneration in preeclampsia: from molecular mechanism toward therapy.

Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with placental dysfunction and vascular maladaptation. Defective remodeling of maternal spiral arteries leads to placental ischemia, a key driver of the maternal systemic syndrome. Extracellular vesicles (EVs) from highly invasive choriocarcinoma trophoblasts, which exhibit pro-angiogenic properties, represent a potential therapeutic resource. However, their utility for targeted therapy in PE remains unexplored. We engineered EVs derived from RGD-JEG-3-EVs on activated vasculature. The therapeutic potential and safety were evaluated in the L-NAME-induced rat model of gestational hypertension and endothelial dysfunction. A combination of in vivo imaging, functional assays in HUVECs, proteomic analysis, and molecular interventions was used to assess efficacy and mechanism. RGD-JEG-3-EVs exhibited preferential placental accumulation, alleviated maternal hypertension and proteinuria, improved fetal growth, and enhanced placental vascular density this model. Short-term tumorigenicity and toxicity assessments revealed no detectable adverse effects under experimental conditions. Proteomic profiling identified FASCIN as a key protein enriched in JEG-3-EVs. Functional studies indicated that FASCIN contributed to EV-mediated pro-angiogenic effects in a Wnt/β-catenin-dependent manner. Suppression of FASCIN attenuated the therapeutic benefits in vivo. This study provides proof-of-concept for using engineered RGD-JEG-3-EVs as a targeted strategy to deliver pro-angiogenic signals (FASCIN-Wnt/β-catenin signal) and improve placental vascular function in a rat model of gestational hypertension, supporting further investigation of this nanotherapeutic strategy.