Trophoblast mitochondrial dysfunction in preeclampsia: Pathology-guided design of fetal-sparing placental nanotherapy.

Abstract

Preeclampsia is driven by placental pathology in which trophoblast stress, mitochondrial dysfunction, and anti-angiogenic signaling contribute to maternal endothelial injury and adverse fetal outcomes. Although nanomedicine offers a potential means of directing therapy to the placenta, placental accumulation alone does not establish productive trophoblast delivery, mitochondrial target engagement, or fetal safety. This review examines the pathological and bioenergetic features of the preeclamptic placenta that should guide nanocarrier design. Evidence linking abnormal placentation, respiratory instability, excessive mitochondrial reactive oxygen species, defective mitochondrial quality control, and soluble fms-like tyrosine kinase-1 release is discussed alongside the delivery consequences of syncytiotrophoblast injury, malperfusion, altered endocytosis, and mitochondrial depolarization. The principal novelty of this review is a sequential placental-mitochondrial targeting strategy designed to improve therapeutic localization while minimizing fetal exposure. In this approach, nanocarriers first accumulate at the maternal-facing placental surface and are subsequently internalized by trophoblast cells. Following cellular uptake, an intracellular trigger activates the previously masked mitochondrial-targeting component, enabling the therapeutic cargo to reach dysfunctional trophoblast mitochondria. This sequential delivery process aims to enhance placental selectivity and mitochondrial drug delivery while restricting transplacental passage into the fetal circulation. Current evidence from mitochondria-targeted antioxidants, placental sFlt-1 silencing, and pro-angiogenic mRNA delivery supports the biological feasibility of this strategy but remains limited by model fidelity, disease heterogeneity, and insufficient developmental safety assessment. Future translation will require pathology-calibrated human placental models, direct comparison of staged and constitutive targeting systems, quantitative maternal-placental-fetal biodistribution, and long-term evaluation of placental compatibility and offspring safety.

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