The efficient delivery of antisense oligonucleotides (ASOs) to the targeted cells and organs remains a challenge, in particular, in vivo. Here, we investigated the ability of a library of biodegradable lipid nanoparticles (LNPs) in delivering ASO to both cultured human cells and animal models. We first identified three top-performing lipids through in vitro screening using GFP-expressing HEK293 cells. Next, we explored these three candidates for delivering ASO to target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in mice. We found that lipid 306-O12B-3 showed efficiency with the median effective dose (ED50) as low as 0.034 mg·kg-1, which is a notable improvement over the efficiency reported in the literature. No liver or kidney toxicity was observed with a dose up to 5 mg·kg-1 of this ASO/LNP formulation. The biodegradable LNPs are efficient and safe in the delivery of ASO and pave the way for clinical translation.

中文翻译：

---

使用可生物还原的脂质纳米颗粒在体内和体内有效递送反义寡核苷酸。

将反义寡核苷酸（ASO）有效递送至靶细胞和器官仍然是一个挑战，特别是在体内。在这里，我们研究了可生物降解的脂质纳米颗粒（LNP）库在将ASO传递到培养的人类细胞和动物模型中的能力。我们首先通过使用表达GFP的HEK293细胞进行体外筛选，确定了三种表现最佳的脂质。接下来，我们探索了这三种将ASO递送至小鼠中的前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型（PCSK9）mRNA的候选物。我们发现脂质306-O12B-3在中值有效剂量（ED50）低至0.034 mg·kg-1时显示出效率，这是对文献报道的效率的显着改善。最高剂量为5 mg·kg-1的ASO / LNP制剂未观察到肝或肾毒性。