基于核苷(酸)脂材的核酸药物纳米制剂体系研究进展

doi:10.16288/j.yczz.24-378

遗传 ›› 2025, Vol. 47 ›› Issue (8): 823-841.doi: 10.16288/j.yczz.24-378

基于核苷(酸)脂材的核酸药物纳米制剂体系研究进展

洪佳美(), 刘泓毅(), 郭华, 于晶, 张琦, 关注, 杨振军()

北京大学药学院，天然药物及仿生药物全国重点实验室，北京 100191

收稿日期:2025-02-19 修回日期:2025-05-08 出版日期:2025-05-09 发布日期:2025-05-09
通讯作者: 杨振军，博士，教授，研究方向：核酸药物及其化学生物学研究。E-mail: yangzj@bjmu.edu.cn
作者简介:洪佳美，博士研究生，专业方向：药物化学专业。E-mail: m17802277004@163.com
刘泓毅，博士研究生，专业方向：药物化学专业。E-mail: hongyiliu@stu.pku.edu.cn
第一联系人：
洪佳美和刘泓毅并列第一作者。
基金资助:
北京市科学技术委员会北京科技计划项目(Z231100004823026)

Progress on nucleos(t)idyl lipid-based nanoparticles for nucleic acid drugs delivery

Jiamei Hong(), Hongyi Liu(), Hua Guo, Jing Yu, Qi Zhang, Zhu Guan, Zhenjun Yang()

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

Received:2025-02-19 Revised:2025-05-08 Published:2025-05-09 Online:2025-05-09
Supported by:
Beijing Science and Technology Commission Beijing Science and Technology Plan Project(Z231100004823026)

摘要/Abstract

摘要：

核酸类药物能够在基因水平发挥作用，具有合成简单、易于修饰、特异性高等优势。然而，相对于传统小分子药物，核酸类药物分子量较大、亲水性高且呈负电性，使其在体内组织递送和靶细胞摄入等方面存在障碍。脂质纳米粒(lipid nanoparticles, LNP)能够通过静电相互作用包载siRNA或mRNA，截至2025年4月已有5种相关药物上市，但由于不可避免的免疫原性及肝脾毒性，相关药物多数终止在临床试验初期。核苷(酸)脂材是一类由碱基或核苷(酸)头部、连接基团和脂质尾链组成的两亲性分子，其头部能够通过氢键、π-π堆积作用与核酸碱基结合并自组装形成纳米颗粒或胶束，具有广阔的应用前景。本文总结了基于其联合肽类阳离子脂材的核酸纳米制剂体系研究进展，并从结构表征、分子动力学模拟、体内分布、体内外药效与安全性等方面对相关制剂进行了分析讨论，为改善药物的体内器官及组织有效递送提供新思路。

关键词: 核酸药物, 核苷(酸)脂材, 脂质纳米粒, 体内递送

Abstract:

Nucleic acid drugs can function at the gene level, and have the advantages of simple synthesis, easy modification and high specificity. However, there are many obstacles in transfection and in vivo delivery due to their negative charge, high molecular weight, and hydrophilicity. Lipid nanoparticles (LNPs) can encapsulate siRNA or mRNA through electrostatic interactions and five related drugs have been approved as of April 2025. However, due to the inevitable immunogenicity and hepatosplenic toxicity, most LNP-encapsulated nucleic acid drugs were terminated in the early clinical stage. Nucleos(t)idyl lipids are a class of amphiphilic molecules composed of nucleobases or nucleos(t)idyl heads, linkers and lipid tail chains, which can bind with the bases of nucleic acid drugs through hydrogen bonding and π-π stacking and self-assemble to form nanoparticles or micelles with broad application prospects. In this review, we summarize the research progress in delivery systems of nucleic acid drugs based on nucleos(t)idyl lipids and peptidyl lipids, and discuss their differences with LNP-encapsulated nucleic acid drugs, including structural characterization, molecular dynamics simulation, in vivo distribution, as well as efficacy and safety, so as to provide new ideas for improving the targeting delivery of nucleic acid drugs.

Key words: nucleic acid drugs, nucleos(t)idyl lipids, lipid nanoparticles, in vivo delivery

洪佳美, 刘泓毅, 郭华, 于晶, 张琦, 关注, 杨振军. 基于核苷(酸)脂材的核酸药物纳米制剂体系研究进展[J]. 遗传, 2025, 47(8): 823-841.

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.

图/表 11

表1

已上市的核酸类药物"

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)
适配体	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)

表1

图1

表2

图2

图3

图4

表3

图5

表4

表5

图6

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内容	LNP	核苷(酸)脂材
组成成分	可电离脂材/两性离子脂材/胆固醇/DSPE-PEG	核苷(酸)脂材/阳离子脂材/靶向脂材
结合力	静电相互作用	氢键/π-π堆积作用/静电相互作用
稳定性	受离子浓度影响大	多层结构稳定性高
体内分布	SORT/mRNA可用于肝、脾、肺靶向	肝、肺及胰腺肿瘤靶向
安全性	可电离脂材明显炎症反应	DNCA最大耐受量为300 mg/kg

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

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

基于核苷(酸)脂材的核酸药物纳米制剂体系研究进展

Progress on nucleos(t)idyl lipid-based nanoparticles for nucleic acid drugs delivery

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核酸种类	100 g脂材载药量(g)		安全性
核酸种类	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