Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs.
Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs.
复制标题
用于将雾化治疗性mRNA递送至肺的脂质纳米颗粒的优化。
DOI：
10.1038/s41551-021-00786-x
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发表时间：
2021-09
影响因子：
28.1
通讯作者：
中科院分区：
文献类型：
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作者：
用于有效递送药物的脂质纳米粒（LNP）需要针对特定的给药途径和药物类型进行设计。在这里，我们报告了LNP的设计，用于通过雾化将治疗性RNA有效递送至肺。我们优化了脂质，中性或阳离子辅助脂质和聚（乙二醇）（PEG）的LNP的组成，摩尔比和结构的LNP的性能进行评估属于六个集群占据极端的化学空间，然后汇集的铅集群和扩大其多样性。我们发现，低（高）摩尔比的PEG改善了具有中性（阳离子）辅助脂质的LNP的性能，这是一种用于低剂量信使RNA递送的经鉴定的最佳LNP。通过优化的LNP雾化递送编码靶向血凝素的广泛中和抗体的mRNA保护小鼠免受甲型流感病毒H1N1亚型的致命攻击，并且比先前针对全身递送优化的LNP更有效地递送mRNA。LNP设计的聚类方法可以促进用于其他施用途径和治疗的LNP的优化。
Lipid nanoparticles (LNPs) for the efficient delivery of drugs need to be designed for the particular administration route and type of drug. Here we report the design of LNPs for the efficient delivery of therapeutic RNAs to the lung via nebulization. We optimized the composition, molar ratios and structure of LNPs made of lipids, neutral or cationic helper lipids and poly(ethylene glycol) (PEG) by evaluating the performance of LNPs belonging to six clusters occupying extremes in chemical space, and then pooling the lead clusters and expanding their diversity. We found that a low (high) molar ratio of PEG improves the performance of LNPs with neutral (cationic) helper lipids, an identified and optimal LNP for low-dose messenger RNA delivery. Nebulized delivery of an mRNA encoding a broadly neutralizing antibody targeting haemagglutinin via the optimized LNP protected mice from a lethal challenge of the H1N1 subtype of influenza A virus, and delivered mRNA more efficiently than LNPs previously optimized for systemic delivery. A cluster approach to LNP design may facilitate the optimization of LNPs for other administration routes and therapeutics.
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DOI：
10.1038/mtna.2014.61
发表时间：
2014-11-18
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
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影响因子：
10.8
作者：
Kauffman, Kevin J.;Dorkin, J. Robert;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.
影响因子：
15
作者：
Chen, Delai;Love, Kevin T.;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.
影响因子：
16.6
作者：
Jayaraman, Muthusamy;Ansell, Steven M.;Mui, Barbara L.;Tam, Ying K.;Chen, Jianxin;Du, Xinyao;Butler, David;Eltepu, Laxman;Matsuda, Shigeo;Narayanannair, Jayaprakash K.;Rajeev, Kallanthottathil G.;Hafez, Ismail M.;Akinc, Akin;Maier, Martin A.;Tracy, Mark A.;Cullis, Pieter R.;Madden, Thomas D.;Manoharan, Muthiah;Hope, Michael J.
通讯作者：
Hope, Michael J.
DOI：
10.1056/nejmoa2035389
发表时间：
2021-02-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Baden LR;El Sahly HM;Essink B;Kotloff K;Frey S;Novak R;Diemert D;Spector SA;Rouphael N;Creech CB;McGettigan J;Khetan S;Segall N;Solis J;Brosz A;Fierro C;Schwartz H;Neuzil K;Corey L;Gilbert P;Janes H;Follmann D;Marovich M;Mascola J;Polakowski L;Ledgerwood J;Graham BS;Bennett H;Pajon R;Knightly C;Leav B;Deng W;Zhou H;Han S;Ivarsson M;Miller J;Zaks T;COVE Study Group
通讯作者：
COVE Study Group