Preeclampsia (PE) poses a significant threat to maternal and fetal health, characterized by hypertension during pregnancy. This study investigates a promising approach to combat PE utilizing nanotechnology for the targeted delivery of short-chain fatty acids. By leveraging a sol-gel method and chemical deposition, cerium oxide-coated mesoporous silica nanoparticles loaded with sodium butyrate (CeO₂@MSN@SB) were synthesized. The innovative strategy focuses on modulating gut microbiota and JunB proto-oncogene (JUNB) gene expression to induce macrophage M2 polarization and facilitate vascular remodeling. Evaluation in PE mouse models revealed that CeO₂@MSN@SB effectively improved blood pressure, urinary protein levels, placental function, and gut microbiota composition. Furthermore, the nanoparticles exhibited the ability to regulate key genes related to angiogenesis and inflammation, notably JUNB, leading to enhanced macrophage M2 polarization, trophoblast functionality, and vascular restructuring. These findings highlight that the application of nanotechnology holds potential to advance PE prevention and therapy.

Preeclampsia (PE) is a serious pregnancy-related disorder characterized by dysregulated glycolysis and aberrant histone lactylation in the placenta. In this study, we developed folic acid (FA)-modified lipid nanoparticles (FA-LNPs) encapsulating small interfering RNA targeting pyruvate kinase M (si-PKM), termed FA-LNP@si-PKM, to specifically modulate the molecular drivers of PE. Integrated transcriptomic and proteomic profiling identified PKM as a critical regulator in PE pathogenesis, associated with excessive lactate production and increased histone H3 lysine 18 (H3K18) lactylation. Further mechanistic studies revealed that the histone acetyltransferase lysine acetyltransferase 7 (KAT7) plays a pivotal role in mediating this lactylation process. In vitro silencing of PKM significantly reduced lactate accumulation, suppressed H3K18 lactylation, and attenuated pro-inflammatory cytokine production. Conversely, KAT7 overexpression abrogated these effects, highlighting its essential role in the PKM-lactate-H3K18la axis. In vivo, systemic administration of FA-LNP@si-PKM in an L-NAME-induced murine model of PE led to marked improvements, including reduced systolic blood pressure and proteinuria, diminished placental H3K18la levels, and lower expression of inflammatory markers IL-6 and TNF-α. These findings underscore the therapeutic potential of targeting the KAT7-H3K18la signaling axis using FA-LNP-mediated siRNA delivery. This nanotechnology-based approach offers a promising strategy for addressing the molecular etiology of PE and enhancing maternal and fetal outcomes.