Ionizable lipid nanoparticles for in utero mRNA delivery.
Ionizable lipid nanoparticles for in utero mRNA delivery.
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DOI：
10.1126/sciadv.aba1028
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发表时间：
2021-01
期刊：
影响因子：
13.6
通讯作者：
Mitchell MJ
中科院分区：
文献类型：
--
作者：
Riley RS;Kashyap MV;Billingsley MM;White B;Alameh MG;Bose SK;Zoltick PW;Li H;Zhang R;Cheng AY;Weissman D;Peranteau WH;Mitchell MJ
脂质纳米颗粒将mRNA递送到小鼠胎儿，这可能最终使子宫内疗法能够治疗胎儿遗传疾病。临床进展使遗传疾病的产前诊断成为可能，这些遗传疾病是基因和酶疗法的候选者，如信使RNA（mRNA）介导的蛋白质替代。产前mRNA疗法可以在不可逆病理发生之前治疗疾病，由于胎儿尺寸小、免疫系统不成熟和祖细胞丰富，因此具有高疗效和安全性。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，用于子宫内mRNA递送至小鼠胎儿。我们筛选了用于荧光素酶mRNA递送的LNP，并鉴定了与基准递送系统DLin-MC 3-DMA和jetPEI相比具有更高效率和安全性的在胎儿肝、肺和肠内积累的制剂。我们证明LNP可以递送mRNA以诱导治疗性分泌蛋白的肝脏产生。这些LNP可以提供用于蛋白质替换和基因编辑的子宫内mRNA递送的平台。
Lipid nanoparticles deliver mRNA to mouse fetuses, which may ultimately enable in utero therapy to treat fetal genetic diseases. 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.
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