Cytokine mRNA Delivery and Local Immunomodulation in the Placenta Using Lipid Nanoparticles

IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Samuel I. Hofbauer, Luisa A. Fink, Rachel E. Young, Tara Vijayakumar, Katherine M. Nelson, Nia Bellopede, Mohamad-Gabriel Alameh, Drew Weissman, Jason P. Gleghorn, Rachel S. Riley
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Abstract

During pregnancy, the maternal immune system adapts to balance tolerance of the semi-allogenic fetus while protecting the fetus from pathogens. Dysregulated immune activity at the maternal–fetal interface contributes to pregnancy complications, such as recurrent pregnancy loss and preeclampsia. Compared to healthy placentas, preeclamptic placentas exhibit increased pro-inflammatory signaling, including a predominance of inflammatory macrophages, leading to impaired tissue remodeling and restricted blood flow. However, the precise mechanisms driving this immune imbalance remain poorly understood, in part due to the lack of tools to probe individual pathways. Here, lipid nanoparticles (LNPs) are used to deliver cytokine-encoded mRNA to placental cells, called trophoblasts, enabling local immunomodulation. LNP-mediated delivery of IL-4 and IL-13 mRNA induced cytokine secretion by trophoblasts, leading to polarization of primary human monocytes toward anti-inflammatory phenotypes. Notably, lowering the mRNA dose increased expression of alternatively-activated macrophage markers, revealing an inverse relationship between dose and polarization status. Intravenous injection of LNPs in pregnant mice achieves placental secretion of IL-4 and IL-13 with minimal changes to pro-inflammatory cytokines in the serum. These findings establish LNPs as tools for local immunomodulation in the placenta, offering a strategy to study and treat immune dysfunction in pregnancy and in other inflammatory conditions.

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细胞因子mRNA在胎盘中的传递和局部免疫调节
在怀孕期间,母体免疫系统适应平衡半异体胎儿的耐受性,同时保护胎儿免受病原体的侵害。在母胎界面的免疫活动失调有助于妊娠并发症,如复发性妊娠丢失和先兆子痫。与健康胎盘相比,子痫前期胎盘表现出增加的促炎信号,包括炎性巨噬细胞的优势,导致组织重塑受损和血流受限。然而,驱动这种免疫失衡的确切机制仍然知之甚少,部分原因是缺乏探测个体途径的工具。在这里,脂质纳米颗粒(LNPs)被用来将细胞因子编码的mRNA传递到胎盘细胞,称为滋养层细胞,从而实现局部免疫调节。lnp介导的IL-4和IL-13 mRNA的传递诱导滋养层细胞分泌细胞因子,导致人原代单核细胞向抗炎表型极化。值得注意的是,降低mRNA剂量可增加选择性活化巨噬细胞标志物的表达,表明剂量与极化状态呈反比关系。妊娠小鼠静脉注射LNPs可使胎盘分泌IL-4和IL-13,而血清中促炎因子的变化极小。这些发现确立了LNPs作为胎盘局部免疫调节的工具,为研究和治疗妊娠期和其他炎症条件下的免疫功能障碍提供了策略。
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来源期刊
Advanced Therapeutics
Advanced Therapeutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.10
自引率
2.20%
发文量
130
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