Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach.
Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach.
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DOI：
10.1016/j.bioactmat.2023.11.014
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发表时间：
2024-04
影响因子：
18.9
通讯作者：
中科院分区：
文献类型：
--
作者：
作为COVID-19疫苗接种和蛋白质替代疗法的mRNA递送平台，可电离脂质纳米颗粒（LNPs）受到了关注。与没有载体平台的mRNA相比，LNPs增强了mRNA的稳定性、循环时间、细胞摄取和向特定组织的优先递送。然而，LNPs在安全有效地将mRNA传递到胎盘以治疗胎盘功能障碍方面仅处于发展的初级阶段。在这里，我们开发的LNPs能够在体外将高水平的mRNA递送到滋养细胞和体内的胎盘，而没有毒性。我们进行了一项实验设计，以探索LNP的组成，包括每种脂质成分的类型和摩尔比，如何驱动滋养细胞和胎盘的分娩。我们的数据显示，在LNP设计中，以C12-200作为可电离脂质，以1,2-二油基-锡-甘油-3-磷酸乙醇胺（DOPE）作为磷脂，可以获得较高的体外转染效率。作为LNPs设计参数的脂质摩尔组成分析显示，表观pKa与聚乙二醇（PEG）含量之间存在很强的相关性，因为PEG摩尔量的减少会增加表观pKa。此外，我们提出了一种LNP平台，该平台显示胎盘生长因子mRNA在妊娠小鼠胎盘中的最高递送，导致潜在治疗蛋白的合成和分泌。最后，我们的高性能LNPs对怀孕小鼠和胎儿都没有毒性。我们的研究结果证明了LNP作为mRNA传递到胎盘的平台的可行性，我们的顶级LNP配方可能为治疗妊娠期间胎盘功能障碍引起的疾病提供治疗平台。C12-200和DOPE可提高滋养细胞mRNA的转染效率。PEG摩尔量的减少使LNPs的表观pKa增加。LNPs向妊娠小鼠胎盘传递治疗性mRNA。LNPs对胎儿没有毒性。
Ionizable lipid nanoparticles (LNPs) have gained attention as mRNA delivery platforms for vaccination against COVID-19 and for protein replacement therapies. LNPs enhance mRNA stability, circulation time, cellular uptake, and preferential delivery to specific tissues compared to mRNA with no carrier platform. However, LNPs are only in the beginning stages of development for safe and effective mRNA delivery to the placenta to treat placental dysfunction. Here, we develop LNPs that enable high levels of mRNA delivery to trophoblasts in vitro and to the placenta in vivo with no toxicity. We conducted a Design of Experiments to explore how LNP composition, including the type and molar ratio of each lipid component, drives trophoblast and placental delivery. Our data revealed that utilizing C12-200 as the ionizable lipid and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as the phospholipid in the LNP design yields high transfection efficiency in vitro. Analysis of lipid molar composition as a design parameter in LNPs displayed a strong correlation between apparent pKa and poly (ethylene) glycol (PEG) content, as a reduction in PEG molar amount increases apparent pKa. Further, we present one LNP platform that exhibits the highest delivery of placental growth factor mRNA to the placenta in pregnant mice, resulting in synthesis and secretion of a potentially therapeutic protein. Lastly, our high-performing LNPs have no toxicity to both the pregnant mice and fetuses. Our results demonstrate the feasibility of LNPs as a platform for mRNA delivery to the placenta, and our top LNP formulations may provide a therapeutic platform to treat diseases that originate from placental dysfunction during pregnancy. C12-200 and DOPE increase transfection efficiency of mRNA in trophoblasts. Reduction in PEG molar amount increases apparent pKa of LNPs. LNPs deliver therapeutic mRNA to the placenta in pregnant mice. LNPs exhibit no toxicity to fetuses.
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影响因子：
5.1
作者：
DeRosa, F.;Guild, B.;Karve, S.;Smith, L.;Love, K.;Dorkin, J. R.;Kauffman, K. J.;Zhang, J.;Yahalom, B.;Anderson, D. G.;Heartlein, M. W.
通讯作者：
Heartlein, M. W.
影响因子：
32.4
作者：
Alameh MG;Tombácz I;Bettini E;Lederer K;Sittplangkoon C;Wilmore JR;Gaudette BT;Soliman OY;Pine M;Hicks P;Manzoni TB;Knox JJ;Johnson JL;Laczkó D;Muramatsu H;Davis B;Meng W;Rosenfeld AM;Strohmeier S;Lin PJC;Mui BL;Tam YK;Karikó K;Jacquet A;Krammer F;Bates P;Cancro MP;Weissman D;Luning Prak ET;Allman D;Locci M;Pardi N
通讯作者：
Pardi N
影响因子：
5.9
作者：
Carrasco MJ;Alishetty S;Alameh MG;Said H;Wright L;Paige M;Soliman O;Weissman D;Cleveland TE 4th;Grishaev A;Buschmann MD
通讯作者：
Buschmann MD
影响因子：
2.6
作者：
Andrikos A;Andrikos D;Schmidt B;Birdir C;Kimmig R;Gellhaus A;Köninger A
通讯作者：
Köninger A
DOI：
10.1073/pnas.2109256118
发表时间：
2021-12-28
影响因子：
11.1
作者：
Dilliard, Sean A.;Cheng, Qiang;Siegwart, Daniel J.
通讯作者：
Siegwart, Daniel J.