Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)–mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.

临床进展使得遗传病的产前诊断成为可能，这些遗传病是基因和酶疗法的候选者，例如信使 RNA (mRNA) 介导的蛋白质替代。由于胎儿体积小、免疫系统不成熟和祖细胞丰富，产前 mRNA 疗法可以在不可逆病理发生之前治疗疾病，具有较高的治疗效果和安全性。然而，用于产前分娩的非​​病毒平台的开发才刚刚起步。我们开发了一个可电离脂质纳米颗粒 (LNP) 库，用于在子宫内将 mRNA 递送至小鼠胎儿。我们筛选了用于荧光素酶 mRNA 递送的 LNP，并确定了与基准递送系统、DLin-MC3-DMA 和 jetPEI 相比，在胎儿肝脏、肺和肠道内积累的制剂具有更高的效率和安全性。我们证明 LNP 可以传递 mRNA 来诱导肝脏产生治疗性分泌蛋白。这些 LNP 可能为子宫内 mRNA 传递提供平台，以进行蛋白质替换和基因编辑。