Loss-of-function mutations in Angiopoietin-like 3 (Angptl3) are associated with lowered blood lipid levels, making Angptl3 an attractive therapeutic target for the treatment of human lipoprotein metabolism disorders. In this study, we developed a lipid nanoparticle delivery platform carrying Cas9 messenger RNA (mRNA) and guide RNA for CRISPR-Cas9–based genome editing of Angptl3 in vivo. This system mediated specific and efficient Angptl3 gene knockdown in the liver of wild-type C57BL/6 mice, resulting in profound reductions in serum ANGPTL3 protein, low density lipoprotein cholesterol, and triglyceride levels. Our delivery platform is significantly more efficient than the FDA-approved MC-3 LNP, the current gold standard. No evidence of off-target mutagenesis was detected at any of the nine top-predicted sites, and no evidence of toxicity was detected in the liver. Importantly, the therapeutic effect of genome editing was stable for at least 100 d after a single dose administration. This study highlights the potential of LNP-mediated delivery as a specific, effective, and safe platform for Cas9-based therapeutics.

血管生成素样 3 ( Angptl3 ) 的功能丧失突变与血脂水平降低相关，这使得Angptl3成为治疗人类脂蛋白代谢紊乱的有吸引力的治疗靶点。在这项研究中，我们开发了一种脂质纳米颗粒递送平台，该平台携带 Cas9 信使 RNA (mRNA) 和引导 RNA，用于基于 CRISPR-Cas9 的体内Angptl3基因组编辑。该系统在野生型 C57BL/6 小鼠的肝脏中介导特异性且有效的Angptl3基因敲除，导致血清 ANGPTL3 蛋白、低密度脂蛋白胆固醇和甘油三酯水平显着降低。我们的递送平台比 FDA 批准的当前黄金标准 MC-3 LNP 效率显着提高。在九个最高预测位点中的任何一个都没有检测到脱靶诱变的证据，并且在肝脏中没有检测到毒性的证据。重要的是，单剂量给药后，基因组编辑的治疗效果至少可以稳定100天。这项研究强调了 LNP 介导的递送作为基于 Cas9 的治疗的特定、有效和安全平台的潜力。