Innovative nanoparticle-based approach for preeclampsia treatment through inhibition of KAT7-mediated histone modifications

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.