The replacement of helper lipids with charged alternatives in lipid nanoparticles facilitates targeted mRNA delivery to the spleen and lungs.
The replacement of helper lipids with charged alternatives in lipid nanoparticles facilitates targeted mRNA delivery to the spleen and lungs.
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DOI：
10.1016/j.jconrel.2022.03.046
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发表时间：
2022-05
影响因子：
10.8
通讯作者：
Whitehead, Kathryn A.
中科院分区：
文献类型：
--
作者：
LoPresti, Samuel T.;Arral, Mariah L.;Chaudhary, Namit;Whitehead, Kathryn A.
mRNA治疗剂的广泛临床应用受到缺乏诱导肝外器官和组织中蛋白质表达的递送载体的阻碍。最近，显示在将带电脂质添加到标准四组分脂质纳米颗粒制剂中后，mRNA递送到脾或肺是可能的。这种方法虽然有效，但使已经复杂的药物制剂进一步复杂化，并有可能减缓监管批准并对制造过程产生不利影响。因此，我们的动机是保持一个四组分的纳米粒子系统，同时实现向性的转变。为此，我们用八种替代品中的一种取代了类胡萝卜素纳米颗粒中的标准辅助脂质DOPE。这些脂质包括中性脂质、DOPC、鞘磷脂和神经酰胺;阴离子脂质、磷脂酰丝氨酸（PS）、磷脂酰甘油和磷脂酸;以及阳离子脂质、DOTAP和乙基磷脂酰胆碱。虽然中性辅助脂质维持蛋白质在肝脏中的表达，但阴离子和阳离子脂质分别将蛋白质表达转移到脾和肺。例如，用DOTAP代替DOPE使pH 7下的正LNP表面电荷增加5倍，并将肝与肺蛋白表达的比率从36：1改变为1：56。类似地，用PS替换DOPE使正电荷减少一半，并将肝脏与脾脏蛋白表达的比率从8：1改变为1：3。在可电离的类青蒿素化学物质中，效果是一致的。关于机制，用中性和阴离子辅助脂质配制的纳米颗粒分别最好地转染上皮细胞和免疫细胞。此外，与中性或阴离子脂质相比，DOTAP的趋肺作用与肺的免疫细胞浸润减少有关。总之，这些数据表明，静脉内非肝细胞mRNA递送是容易实现的，同时保持具有修饰的辅助脂质化学的四组分制剂。
The broad clinical application of mRNA therapeutics has been hampered by a lack of delivery vehicles that induce protein expression in extrahepatic organs and tissues. Recently, it was shown that mRNA delivery to the spleen or lungs is possible upon the addition of a charged lipid to a standard four-component lipid nanoparticle formulation. This approach, while effective, further complicates an already complex drug formulation and has the potential to slow regulatory approval and adversely impact manufacturing processes. We were thus motivated to maintain a four-component nanoparticle system while achieving shifts in tropism. To that end, we replaced the standard helper lipid in lipidoid nanoparticles, DOPE, with one of eight alternatives. These lipids included the neutral lipids, DOPC, sphingomyelin, and ceramide; the anionic lipids, phosphatidylserine (PS), phosphatidylglycerol, and phosphatidic acid; and the cationic lipids, DOTAP and ethyl phosphatidylcholine. While neutral helper lipids maintained protein expression in the liver, anionic and cationic lipids shifted protein expression to the spleen and lungs, respectively. For example, replacing DOPE with DOTAP increased positive LNP surface charge at pH 7 by 5-fold and altered the ratio of liver to lung protein expression from 36:1 to 1:56. Similarly, replacing DOPE with PS reduced positive charge by half and altered the ratio of liver to spleen protein expression from 8:1 to 1:3. Effects were consistent across ionizable lipidoid chemistries. Regarding mechanism, nanoparticles formulated with neutral and anionic helper lipids best transfected epithelial and immune cells, respectively. Further, the lung-tropic effect of DOTAP was linked to reduced immune cell infiltration of the lungs compared to neutral or anionic lipids. Together, these data show that intravenous non-hepatocellular mRNA delivery is readily achievable while maintaining a four-component formulation with modified helper lipid chemistry.
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影响因子：
4.6
作者：
Ball RL;Bajaj P;Whitehead KA
通讯作者：
Whitehead KA
影响因子：
3.4
作者：
Ciani, L;Ristori, S;Martini, G
通讯作者：
Martini, G
影响因子：
8
作者：
Fröhlich E
通讯作者：
Fröhlich E
DOI：
10.1016/j.omtn.2018.02.003
发表时间：
2018-06-01
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
de Groot AM;Thanki K;Gangloff M;Falkenberg E;Zeng X;van Bijnen DCJ;van Eden W;Franzyk H;Nielsen HM;Broere F;Gay NJ;Foged C;Sijts AJAM
通讯作者：
Sijts AJAM
辅助脂质对脂多复合物制剂 DNA 转染效率的作用。
影响因子：
4.6
作者：
Du Z;Munye MM;Tagalakis AD;Manunta MD;Hart SL
通讯作者：
Hart SL