CRISPR-Cas9 has emerged as a powerful technology that relies on Cas9/sgRNA ribonucleoprotein complexes (RNPs) to target and edit DNA. However, many therapeutic targets cannot currently be accessed due to the lack of carriers that can deliver RNPs systemically. Here, we report a generalizable methodology that allows engineering of modified lipid nanoparticles to efficiently deliver RNPs into cells and edit tissues including muscle, brain, liver, and lungs. Intravenous injection facilitated tissue-specific, multiplexed editing of six genes in mouse lungs. High carrier potency was leveraged to create organ-specific cancer models in livers and lungs of mice though facile knockout of multiple genes. The developed carriers were also able to deliver RNPs to restore dystrophin expression in DMD mice and significantly decrease serum PCSK9 level in C57BL/6 mice. Application of this generalizable strategy will facilitate broad nanoparticle development for a variety of disease targets amenable to protein delivery and precise gene correction approaches.

CRISPR-Cas9 已成为一种强大的技术，它依赖于 Cas9/sgRNA 核糖核蛋白复合物 (RNP) 来靶向和编辑 DNA。然而，由于缺乏可以系统地传递 RNP 的载体，目前许多治疗靶点无法获得。在这里，我们报告了一种可推广的方法，该方法允许对修饰的脂质纳米颗粒进行工程改造，以有效地将 RNP 递送到细胞中并编辑包括肌肉、大脑、肝脏和肺在内的组织。静脉注射促进了小鼠肺中六个基因的组织特异性、多重编辑。通过轻松敲除多个基因，利用高载体效力在小鼠肝脏和肺中创建器官特异性癌症模型。开发的载体还能够递送 RNP 以恢复 DMD 小鼠中肌营养不良蛋白的表达，并显着降低 C57BL/6 小鼠中的血清 PCSK9 水平。这种可推广策略的应用将促进广泛的纳米粒子开发，适用于蛋白质递送和精确基因校正方法的各种疾病靶点。