Abstract
Pre-eclampsia (PE) is a placenta-originated pregnancy disorder and a leading cause of maternal-fetal morbidity and mortality worldwide. Aspirin is the only widely recommended evidence-based prophylaxis for PE, yet its therapeutic potential is constrained by limited placental exposure and concerns with long-term dosing. To address these issues, this study engineered an aspirin-RGDV tetrapeptide conjugate (A-RGDV) that self-assembled into serum-stable nanostructures capable of selectively targeting placental integrin αV. The designed A-RGDV showed negligible hemolytic activity and no detectable cytotoxicity toward HTR-8/SVneo trophoblast cells across a concentration range of 5-200 μg/mL. Under CoCl₂ hypoxia-mimetic stress, A-RGDV improved trophoblast viability beyond equimolar aspirin and reduced total apoptosis from 34.6% (model) to 13.6%, versus 23.4% with aspirin. Pharmacokinetic studies revealed that nanoconjugates improved the in vivo behavior of aspirin, evidenced by prolonged plasma retention and an increased area under the concentration-time curve. Tissue distribution studies confirmed pronounced placental enrichment of A-RGDV, with placental drug levels increased by over 50-fold at both 2 h and 6 h compared with aspirin, while fetal exposure was markedly reduced. In an L-NAME-induced murine PE model, A-RGDV more effectively attenuated gestational hypertension than low-dose aspirin, increased fetal and placental weights, and reduced resorption rates to less than 10%. Circulating and placental angiogenic profiles trended toward rebalanced sFlt-1/PlGF, alongside correction of thromboxane/prostacyclin signaling. Collectively, A-RGDV provides integrin-guided placental protection and superior maternal-fetal benefits compared with aspirin, supporting placenta-targeted, dose-sparing therapy for PE.