Multifunctional Nanotherapy Rescues Fetal Growth Restriction via Alleviating Hypoxic Embryonic Microenvironment

Abstract Fetal growth restriction (FGR) is a common pregnancy complication linked to adverse perinatal outcomes, yet effective therapeutic options remain lacking due to insufficient mechanistic understanding. Through integrated analyses of human and rat models of FGR placenta, combined with in‐depth placental cell investigation, it is identified that placental hypoxia triggers oxidative stress, cellular dysfunction, and pro‐inflammatory cytokine activation, collectively contributing to FGR pathogenesis. Building on these findings, a nanotherapeutic platform (PPA NP) is engineered via a one‐pot self‐assembly approach. This formulation incorporates a reactive oxygen species (ROS)‐scavenging unit (PBE), a clinical medication that may prevent FGR (aspirin), and polyethyleneimine (PEI), where PBE and aspirin cooperatively mediated the self‐assembly of PEI. In vitro, PPA NP exerts multiple therapeutic activities, including anti‐apoptotic activity, attenuation of oxidative stress, and enhancement of trophoblast invasion, migration, and endothelial tube formation. In the rat model, PPA NP effectively mitigates FGR by alleviating hypoxia, oxidative stress, vascular injury, and inflammation within the embryonic microenvironment. Critically, PPA NP displays no discernible toxicity to maternal or fetal tissues, even at doses exceeding the therapeutic range. Together, these results highlight PPA NP as a promising and safe nanotherapeutic strategy for FGR, with the potential to address the clinical need for effective interventions in pregnancy complications.