Once inside the cytoplasm of a cell, mRNA can be used to treat disease by upregulating the expression of any gene. Lipid nanoparticles (LNPs) can deliver mRNA to hepatocytes in humans, yet systemic non‐hepatocyte delivery at clinical doses remains difficult. We noted that LNPs have historically been formulated with phospholipids containing unconstrained alkyl tails. Based on evidence that constrained adamantyl groups have unique properties that can improve small molecule drug delivery, we hypothesized that a phospholipid containing an adamantyl group would facilitate mRNA delivery in vivo. We quantified how 109 LNPs containing “constrained phospholipids” delivered mRNA to 16 cell types in mice, then using a DNA barcoding‐based analytical pipeline, related phospholipid structure to in vivo delivery. By analyzing delivery mediated by constrained phospholipids, we identified a novel LNP that delivers mRNA to immune cells at 0.5 mg/kg. Unlike many previous LNPs, these (a) did not preferentially target hepatocytes and (b) delivered mRNA to immune cells without targeting ligands. These data suggest constrained phospholipids may be useful LNP components.

中文翻译：

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含有受约束的磷脂的纳米粒子可在不靶向配体的情况下在体内将mRNA递送至肝脏免疫细胞

一旦进入细胞的细胞质，mRNA可用于通过上调任何基因的表达来治疗疾病。脂质纳米颗粒（LNP）可以将mRNA传递给人类的肝细胞，但是以临床剂量进行全身性非肝细胞传递仍然很困难。我们注意到，LNP历来是用含有不受约束的烷基尾巴的磷脂配制的。基于有证据表明受约束的金刚烷基具有可以改善小分子药物递送的独特性质，我们假设含有金刚烷基的磷脂将促进体内mRNA的递送。我们量化了109种含有“受约束的磷脂”的LNP如何在小鼠中将mRNA传递给16种细胞类型，然后使用基于DNA条形码的分析管道将磷脂的结构与体内传递相关。通过分析受约束的磷脂介导的传递，我们确定了一种新型的LNP，可以以0.5 mg / kg的速度向免疫细胞传递mRNA。与许多以前的LNP不同，这些（a）不会优先靶向肝细胞，并且（b）将mRNA递送至免疫细胞而不靶向配体。这些数据表明受约束的磷脂可能是有用的LNP成分。