Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo.
Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo.
复制标题
哌嗪衍生的脂质纳米颗粒在体内将mRNA传递给免疫细胞。
DOI：
10.1038/s41467-022-32281-5
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发表时间：
2022-08-15
影响因子：
16.6
通讯作者：
Dahlman, James E.
中科院分区：
文献类型：
--
作者：
Ni, Huanzhen;Hatit, Marine Z. C.;Zhao, Kun;Loughrey, David;Lokugamage, Melissa P.;Peck, Hannah E.;Del Cid, Ada;Muralidharan, Abinaya;Kim, YongTae;Santangelo, Philip J.;Dahlman, James E.
在人类中，脂质纳米颗粒（LNP）在全身给药后安全地将治疗性RNA递送至肝细胞，并在肌内注射后安全地递送至抗原呈递细胞。然而，全身RNA递送至非肝细胞仍然具有挑战性，特别是在没有靶向配体如抗体、肽或适体的情况下。在这里，我们报告说，哌嗪含有电离脂质（PI脂质）优先提供mRNA的免疫细胞在体内没有针对配体。在合成和表征Pi-脂质之后，我们使用高通量DNA条形码来量化65种化学上不同的LNP如何功能性地递送mRNA（即，mRNA翻译成功能性的基因编辑蛋白）直接在体内14种细胞类型中。通过分析脂质结构和细胞靶向之间的关系，我们确定了增加体内递送的脂质性状。此外，我们表征了Pi-A10，这是一种LNP，其在临床相关剂量0.3 mg/kg下优先将mRNA递送至肝脏和脾脏免疫细胞。这些数据表明，高通量体内研究可以识别具有天然非肝细胞向性的纳米颗粒，并支持具有生物活性小分子基序的脂质可以在体内递送mRNA的假设。靶向非肝细胞的下一代脂质纳米颗粒可能是重要的临床工具。使用体内DNA条形码，作者鉴定了含有哌嗪的脂质将mRNA递送到免疫细胞而不靶向配体。
In humans, lipid nanoparticles (LNPs) have safely delivered therapeutic RNA to hepatocytes after systemic administration and to antigen-presenting cells after intramuscular injection. However, systemic RNA delivery to non-hepatocytes remains challenging, especially without targeting ligands such as antibodies, peptides, or aptamers. Here we report that piperazine-containing ionizable lipids (Pi-Lipids) preferentially deliver mRNA to immune cells in vivo without targeting ligands. After synthesizing and characterizing Pi-Lipids, we use high-throughput DNA barcoding to quantify how 65 chemically distinct LNPs functionally delivered mRNA (i.e., mRNA translated into functional, gene-editing protein) in 14 cell types directly in vivo. By analyzing the relationships between lipid structure and cellular targeting, we identify lipid traits that increase delivery in vivo. In addition, we characterize Pi-A10, an LNP that preferentially delivers mRNA to the liver and splenic immune cells at the clinically relevant dose of 0.3 mg/kg. These data demonstrate that high-throughput in vivo studies can identify nanoparticles with natural non-hepatocyte tropism and support the hypothesis that lipids with bioactive small-molecule motifs can deliver mRNA in vivo. Next-generation lipid nanoparticles that target non-hepatocytes could be important clinical tools. Using in vivo DNA barcoding, the authors identify piperazine-containing lipids deliver mRNA to immune cells without targeting ligands.
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影响因子：
6.6
作者：
FULTON, A;NORMAN, T;BURROWS, GD
通讯作者：
BURROWS, GD
影响因子：
38.3
作者：
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158.5
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通讯作者：
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作者：
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通讯作者：
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影响因子：
15
作者：
Chen, Delai;Love, Kevin T.;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.