On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles
On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles
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DOI：
10.1073/pnas.2109256118
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发表时间：
2021-12-28
影响因子：
11.1
通讯作者：
Siegwart, Daniel J.
中科院分区：
文献类型：
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作者：
Dilliard, Sean A.;Cheng, Qiang;Siegwart, Daniel J.
脂质纳米颗粒（LNPs）是一种临床成熟的遗传药物递送技术，但由于肝脏积聚，其治疗应用有限。最近，我们的实验室开发了选择性器官靶向（SORT）纳米颗粒，通过将信使RNA （mRNA）和基因编辑系统递送到非肝脏组织，扩大了遗传药物的治疗应用。SORT纳米颗粒包括一个补充的SORT分子，其化学结构决定LNP的组织特异性活性。为了了解SORT纳米颗粒如何超越肝脏肝细胞积聚的传递屏障，我们研究了确定其器官靶向特性的机制因素。我们发现添加的SORT分子的化学性质控制着SORT纳米颗粒的生物分布、全局/表观pKa和血清蛋白相互作用。此外，我们提供了内源性靶向机制的证据，其中器官靶向发生在1)从LNP表面的聚乙二醇脂质的解吸，2)由于暴露的SORT分子的识别，不同的蛋白质结合到纳米颗粒表面，以及3)随后表面结合的蛋白质与特定组织中高度表达的同源受体之间的相互作用。这些发现建立了SORT纳米颗粒的分子组成与其独特而精确的器官靶向特性之间的关键联系，并表明将特定蛋白质募集到纳米颗粒表面可以使药物传递超越肝脏。
Lipid nanoparticles (LNPs) are a clinically mature technology for the delivery of genetic medicines but have limited therapeutic applications due to liver accumulation. Recently, our laboratory developed selective organ targeting (SORT) nanoparticles that expand the therapeutic applications of genetic medicines by enabling delivery of messenger RNA (mRNA) and gene editing systems to non-liver tissues. SORT nanoparticles include a supplemental SORT molecule whose chemical structure determines the LNP's tissue-specific activity. To understand how SORT nanoparticles surpass the delivery barrier of liver hepatocyte accumulation, we studied the mechanistic factors which define their organ-targeting properties. We discovered that the chemical nature of the added SORT molecule controlled biodistribution, global/apparent pKa, and serum protein interactions of SORT nanoparticles. Additionally, we provide evidence for an endogenous targeting mechanism whereby organ targeting occurs via 1) desorption of poly(ethylene glycol) lipids from the LNP surface, 2) binding of distinct proteins to the nanoparticle surface because of recognition of exposed SORT molecules, and 3) subsequent interactions between surfacebound proteins and cognate receptors highly expressed in specific tissues. These findings establish a crucial link between the molecular composition of SORT nanoparticles and their unique and precise organ-targeting properties and suggest that the recruitment of specific proteins to a nanoparticle's surface can enable drug delivery beyond the liver.