Modulating Placental Functionality in Preeclampsia With siRNA Nanocomplexes

BACKGROUND: Early-onset preeclampsia poses significant risks to maternal and fetal health, necessitating a deeper understanding of its molecular mechanisms and effective therapeutic strategies. METHODS: Utilizing data from genome-wide association study and Mendelian randomization analysis, we investigated the relationship between mitochondrial DNA copy number and preeclampsia. Transcriptome sequencing, in vitro experiments, and animal studies were conducted to explore the roles of SENP3 and SETD7 in preeclampsia pathogenesis. The development and evaluation of small interfering RNA (siRNA) SENP3 (SUMO-specific protease 3) delivered by DMD@DPF (D-Lin-MC3-DMA/DSPE-PEG-Folate nanoparticle delivery system) nanoparticles as a potential therapeutic intervention were also performed. RESULTS: Our findings revealed a negative correlation between mitochondrial DNA copy number and preeclampsia, significant differential expression of SENP3 and SETD7 (SET domain containing lysine methyltransferase 7) in preeclampsia placentas, and the therapeutic effects of siRNA SENP3 delivered by DMD@DPF nanoparticles on physiological parameters in a preeclampsia mouse model. CONCLUSIONS: This study highlights the crucial involvement of SENP3 and SETD7 in preeclampsia pathophysiology and proposes siRNA SENP3 delivered by DMD@DPF nanoparticles as a promising therapeutic approach for preeclampsia treatment.