Hereditas(Beijing) ›› 2025, Vol. 47 ›› Issue (8): 823-841.doi: 10.16288/j.yczz.24-378
• Review • Previous Articles Next Articles
Jiamei Hong(), Hongyi Liu(
), Hua Guo, Jing Yu, Qi Zhang, Zhu Guan, Zhenjun Yang(
)
Received:
2025-02-19
Revised:
2025-05-08
Online:
2025-05-09
Published:
2025-05-09
Contact:
Zhenjun Yang
E-mail:m17802277004@163.com;hongyiliu@stu.pku.edu.cn;yangzj@bjmu.edu.cn
Supported by:
Jiamei Hong, Hongyi Liu, Hua Guo, Jing Yu, Qi Zhang, Zhu Guan, Zhenjun Yang. Progress on nucleos(t)idyl lipid-based nanoparticles for nucleic acid drugs delivery[J]. Hereditas(Beijing), 2025, 47(8): 823-841.
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Table 1
The approved nucleic acid drugs"
种类 | 上市 年份 | 通用名/ 商品名 | 适应症 | 给药方式 | 包载/缀合 | 修饰 | 研发公司 |
---|---|---|---|---|---|---|---|
反义 核酸 | 1998 | Fomivirsen/ Vitraveve | 巨细胞病毒性视网膜炎 | 玻璃体注射 | Naked | PS | Ionis Pharmaceuticals (美国) |
2013 | Mipomersen/ Kynamro | 纯合子家族性高胆固醇 血症 | 皮下注射 | Naked | PS, 2′-OMOE | Ionis Pharmaceuticals (美国) | |
2016 | Eteplirsen/ Exongys 51 | 杜氏肌营养不良症 | 静脉注射 | Naked | PMO | Sarepta Therapeutics (美国) | |
2016 | Nusinersen/ Spinraza | 脊髓性肌萎缩症 | 鞘内注射 | Naked | PS, 2′-OMOE | Ionis Pharmaceuticals (美国)/ Biogen (美国) | |
2018 | Inotersen/ Tegsedi | 成人遗传性转甲状腺素 蛋白淀粉样变性 | 皮下注射 | Naked | PS, 2′-OMOE | Ionis Pharmaceuticals (美国)/ Akcea Therapeutics (美国) | |
2019 | Golodirsen/ Vyondys 53 | 杜氏肌营养不良症 | 静脉注射 | Naked | PMO | Sarepta Therapeutics (美国) | |
2019 | Volanesorsen/ Waylivra | 家族性高乳糜微粒血症 | 皮下注射 | Naked | PS, 2′-OMOE | Ionis Pharmaceuticals (美国)/ Akcea Therapeutics (美国) | |
2020 | Viltolarsen/ NS-065 | 杜氏肌营养不良症 | 静脉注射 | Naked | PMO | Nippon Shinyaku (日本) | |
2021 | Casimersen/ Amondys45 | 杜氏肌营养不良症 | 静脉注射 | Naked | PMO | Sarepta Therapeutics (美国) | |
2023 | Tofersen/ Qalsody | SOD1基因突变肌萎缩 侧索硬化症 | 静脉注射 | Naked | PS, 2′-OMOE | Ionis Pharmaceuticals (美国)/ Biogen (美国) | |
2023 | Eplontersen/ Wainua | 转甲状腺素蛋白淀粉样 变性 | 皮下注射 | GalNAc | PS, 2′-OMOE | Ionis Pharmaceuticals (美国)/ Akcea Therapeutics (美国) | |
2024 | Imetelstat/ Rytelo | 骨髓增生异常综合征 | 静脉注射 | C16 | NPS | Geron Corporation (美国) | |
2024 | Olezarsen/ Tryngolza | 家族性乳糜微粒血症 综合征 | 皮下注射 | GalNAc | PS, 2′-OMOE | Ionis Pharmaceuticals (美国) | |
siRNA | 2018 | Patisiran/ Onpattro | 成人遗传性转甲状腺素 蛋白淀粉样变性 | 静脉注射 | LNP | 2′-OMe | Alnylam Pharmaceuticals (美国) |
2019 | Givosiran/ Givlaari | 成人急性肝卟啉病 | 皮下注射 | GalNAc | PS, 2′-OMe, 2′-F | Alnylam Pharmaceuticals (美国) | |
2020 | Lumasiran/ Oxlumo | 原发性高草酸尿症1型 | 皮下注射 | GalNAc | PS, 2′-OMe, 2′-F | Alnylam Pharmaceuticals (美国) | |
2021 | Inclisiran/ Leqvio | 高胆固醇血症血脂异常 | 皮下注射 | GalNAc | PS, 2′-OMe, 2′-F | Novartis (瑞士) | |
2022 | Vutrisiran/ Amvuttra | 成人遗传性转甲状腺素 蛋白淀粉样变性 | 皮下注射 | GalNAc | PS, 2′-OMe, 2′-F | Alnylam Pharmaceuticals (美国) | |
2023 | Nedosiran/ Rivfloza | 原发性高草酸尿症1型 | 皮下注射 | GalNAc | PS, 2′-OMe, 2′-F | Dicerna Pharmaceuticals (美国) | |
2025 | Fitusiran/ Qfitlia | A型或B型血友病 | 皮下注射 | GalNAc | PS, 2′-OMe, 2′-F | Sanofi (法国)/ Alnylam Pharmaceuticals (美国) | |
mRNA | 2021 | Tozinameran/ Comirnaty | 新型冠状病毒感染 | 肌肉注射 | LNP | m1Ψ | BioNTech (德国)/Pfizer(美国) |
2020 | Elasomeran/ SpikeVax | 新型冠状病毒感染 | 肌肉注射 | LNP | m1Ψ | Moderna Therapeutics (美国) | |
2023 | SYS6006/ 度恩泰 | 新型冠状病毒感染 | 肌肉注射 | LNP | m1Ψ | 石药集团(中国) | |
2024 | mRNA-1345/ mRESVIA | 呼吸道合胞病毒感染 | 肌肉注射 | LNP | m1Ψ | Moderna Therapeutics (美国) | |
适配体 | 2004 | Pegaptanib/ Macugen | 年龄相关性黄斑变性 | 眼内注射 | PEG缀合 | 2′-OMe, 2′-F | Eyetech Pharmaceuticals (美国) |
2023 | Avacincaptad Pegol/Izervay | 年龄相关性黄斑变性 引起的地理萎缩 | 眼内注射 | PEG缀合 | 2′-OMe, 2′-F | Astellas Pharma (日本) |
Table 3
Composition and ratio of SORT LNP"
SORT LNP | 组成成分 | 摩尔比例 | 粒径(nm) | PDI | ζ-电位(mV) |
---|---|---|---|---|---|
mDLNP | 5A2-SC8:DOPE:Cholesterol:DMG-PEG2K | 15∶15∶30∶3 | 144.0 | 0.135 | -3.59 |
肝SORT | 5A2-SC8:DOPE:Cholesterol:DMG-PEG2K:DODAP | 15∶15∶30∶3∶15.75 | 154.6 | 0.115 | -3.82 |
脾SORT | 5A2-SC8:DOPE:Cholesterol:DMG-PEG2K:18PA | 15∶15∶30∶3∶27 | 167.8 | 0.144 | -1.84 |
肺SORT | 5A2-SC8:DOPE:Cholesterol:DMG-PEG2K:DOTAP | 15∶15∶30∶3∶63 | 114.8 | 0.159 | -0.89 |
Table 4
LNP-related candidates in phase III clinical trials"
名称 | 适应症 | 种类 | 临床试验号 |
---|---|---|---|
mRNA-4157 | 黑色素瘤; 非小细胞肺癌 | mRNA肿瘤疫苗 | NCT05933577 NCT06077760 |
mRNA-1273 | 带状疱疹 | mRNA病毒疫苗 | NCT05047770 |
mRNA-1647 | 巨细胞病毒感染 | mRNA病毒疫苗 | NCT05085366 |
mRNA-1010 | 季节性流感 | mRNA病毒疫苗 | NCT05415462 |
qlRV | 流感 | mRNA病毒疫苗 | NCT05540522 |
NTLA-2002 | 遗传性血管性 水肿 | sgRNA和 Cas9 mRNA | NCT06634420 |
Table 5
Comparison of loading efficiency and safety of nucleos(t)idyl lipid and LNP-encapsulated nucleic acid drugs"
核酸种类 | 100 g脂材载药量(g) | 安全性 | ||
---|---|---|---|---|
LNP | 核苷(酸)脂材制剂 | LNP | 核苷(酸)脂材制剂 | |
siRNA | 8 | 26 | 炎症反应(Dlin-MC3-DMA<1 mg/kg); DSPE-PEG致产生抗体; 胆固醇含量高(~40%) | 大鼠最大耐受剂量:DNCA 300 mg/kg;CLD 15 mg/kg (未发表数据) |
ASO | / | 22 | ||
适配体 | / | 17 | ||
环二核苷酸 | / | 6 | ||
mRNA疫苗 | 5~8 | 22 |
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