Lipid nanoparticles for delivering mRNA therapeutics hold immense promise for the treatment of a wide range of lung-associated diseases. However, the lack of effective methodologies capable of identifying the pulmonary delivery profile of chemically distinct lipid libraries poses a significant obstacle to the advancement of mRNA therapeutics. Here we report the implementation of a barcoded high-throughput screening system as a means to identify the lung-targeting efficacy of cationic, degradable lipid-like materials. We combinatorially synthesize 180 cationic, degradable lipids which are initially screened in vitro. We then use barcoding technology to quantify how the selected 96 distinct lipid nanoparticles deliver DNA barcodes in vivo. The top-performing nanoparticle formulation delivering Cas9-based genetic editors exhibits therapeutic potential for antiangiogenic cancer therapy within a lung tumor model in female mice. These data demonstrate that employing high-throughput barcoding technology as a screening tool for identifying nanoparticles with lung tropism holds potential for the development of next-generation extrahepatic delivery platforms.

用于传递 mRNA 疗法的脂质纳米粒子对于治疗多种肺部相关疾病具有巨大的前景。然而，缺乏能够识别化学上不同的脂质库的肺部递送特征的有效方法，对 mRNA 治疗的进展构成了重大障碍。在这里，我们报告了条形码高通量筛选系统的实施，作为识别阳离子、可降解类脂材料的肺靶向功效的手段。我们组合合成了 180 种阳离子可降解脂质，并在体外进行了初步筛选。然后，我们使用条形码技术来量化所选的 96 种不同的脂质纳米颗粒如何在体内传递 DNA 条形码。性能最佳的纳米颗粒制剂提供基于 Cas9 的基因编辑器，在雌性小鼠的肺肿瘤模型中表现出抗血管生成癌症治疗的潜力。这些数据表明，采用高通量条形码技术作为筛选工具来识别具有肺向性的纳米颗粒，具有开发下一代肝外递送平台的潜力。