Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions.
Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions.
复制标题
脂质纳米颗粒的物理化学靶向肺部诱导凝血：机制和解决方案。
DOI：
10.1101/2023.07.21.550080
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Brenner,JacobS
中科院分区：
文献类型：
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作者：
Omo-Lamai,Serena;Zamora,MarcoE;Patel,ManthanN;Wu,Jichuan;Nong,Jia;Wang,Zhicheng;Peshkova,Alina;Chase,LiamS;Essien,Eno-Obong;Muzykantov,Vladimir;Marcos-Contreras,Oscar;Myerson,JacobW;Brenner,JacobS
脂质纳米颗粒 (LNP) 已成为行业中占主导地位的药物输送技术，有望输送 RNA 来上调或下调任何感兴趣的蛋白质。 LNP 主要通过物理化学靶向来靶向特定细胞类型或器官，其中 LNP 的脂质成分经过调整以找到具有所需向性的混合物。这里检查了肺向性 LNP，其器官向性源自含有赋予正 zeta 电位的阳离子或可电离脂质。令人惊讶的是，这些 LNP 被发现会诱导大量血栓形成。这种血栓形成出现在肺部和其他器官中，并且表明它会因先前存在的炎症而大大加剧。这种凝血是由多种含有阳离子脂质的制剂诱导的，包括 LNP 和非 LNP 纳米颗粒，甚至是不具有永久阳离子电荷的亲肺可电离脂质。该机制取决于 LNP 与纤维蛋白原结合并改变纤维蛋白原的构象，从而激活血小板和凝血酶。基于这些机制，设计了多种解决方案，使带正电荷的 LNP 能够靶向肺部，同时改善血栓形成。这些发现说明了如何必须尽早研究理化靶向方法的风险，并在仔细了解生物机制的情况下重新设计。
Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up or down‐regulate any protein of interest. LNPs have mostly been targeted to specific cell types or organs by physicochemical targeting in which LNP’s lipid compositions are adjusted to find mixtures with the desired tropism. Here lung‐tropic LNPs are examined, whose organ tropism derives from containing either a cationic or ionizable lipid conferring a positive zeta potential. Surprisingly, these LNPs are found to induce massive thrombosis. Such thrombosis is shown in the lungs and other organs, and it is shown that it is greatly exacerbated by pre‐existing inflammation. This clotting is induced by a variety of formulations with cationic lipids, including LNPs and non‐LNP nanoparticles, and even by lung‐tropic ionizable lipids that do not have a permanent cationic charge. The mechanism depends on the LNPs binding to and then changing the conformation of fibrinogen, which then activates platelets and thrombin. Based on these mechanisms, multiple solutions are engineered that enable positively charged LNPs to target the lungs while ameliorating thrombosis. The findings illustrate how physicochemical targeting approaches must be investigated early for risks and re‐engineered with a careful understanding of biological mechanisms.