Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low-density lipoprotein receptor independent delivery. In low-density lipoprotein receptor-deficient non-human primates administered a CRISPR base editing therapy targeting the ANGPTL3 gene, the introduction of an optimized GalNAc-based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61% with minimal editing in nontargeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing. These results suggest that GalNAc-Lipid nanoparticles may effectively deliver to both patients with intact low-density lipoprotein receptor activity as well as those afflicted by homozygous familial hypercholesterolemia.

脂质纳米颗粒已证明可用于肝脏递送一系列治疗方式，并且通常通过低密度脂蛋白受体介导的内吞作用递送其货物。对于缺乏足够低密度脂蛋白受体活性的患者，例如纯合子家族性高胆固醇血症患者，需要另一种策略。在这里，我们展示了在一系列小鼠和非人类灵长类动物研究中使用结构引导的合理设计来优化 GalNAc-Lipid 纳米颗粒，从而实现低密度脂蛋白受体独立递送。在低密度脂蛋白受体缺陷的非人灵长类动物中，进行了针对 ANGPTL3 的 CRISPR 碱基编辑治疗基因，将优化的基于 GalNAc 的去唾液酸糖蛋白受体配体引入纳米颗粒表面，将肝脏编辑从 5% 增加到 61%，而在非靶向组织中的编辑最少。在野生型猴子中也观察到类似的编辑，给药后六个月血液 ANGPTL3 蛋白持续减少高达 89%。这些结果表明，GalNAc-Lipid 纳米颗粒可以有效地递送给具有完整低密度脂蛋白受体活性的患者以及患有纯合子家族性高胆固醇血症的患者。