Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain
Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain
复制标题
聚焦超声/微泡辅助的血脑屏障开放可增强脂质纳米颗粒（LNP）介导的信使核糖核酸（mRNA）向大脑的递送。
DOI：
10.1016/j.jconrel.2022.05.042
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发表时间：
2022-06-01
影响因子：
10.8
通讯作者：
Kawakami, Shigeru
中科院分区：
文献类型：
--
作者：
Ogawa, Koki;Kato, Naoya;Kawakami, Shigeru
信使RNA （mRNA）药物已成为一种新的治疗方法，这是由于mRNA递送技术的进步，特别是脂质纳米颗粒（LNP）。然而，包裹lnp的mRNA （mRNA- lnp）不能自发地穿过血脑屏障（BBB），而血脑屏障可以阻止外源蛋白在大脑中的表达。微泡辅助聚焦超声（FUS）打开血脑屏障是一项新兴技术，可以瞬间增强血脑屏障的通透性。在这项研究中，研究了FUS/微泡辅助血脑屏障打开，以静脉输送mRNA-LNP到大脑。FUS照射强度优化至1.5 kW/cm(2)，血脑屏障有效开放，无出血或水肿。外源蛋白（荧光素酶）通过mRNA-LNP表达，特别是在FUS照射的脑侧，仅在应用FUS和微泡时发生。这种外源蛋白的表达速度比质粒DNA的传递速度快，但时间短。此外，外源蛋白在小胶质细胞和cd31阳性内皮细胞中表达，而在星形胶质细胞和神经元中未见表达。这些结果支持将mRNA-LNP添加到血脑屏障开口递送的纳米颗粒阵容中。
Messenger RNA (mRNA) medicine has become a new therapeutic approach owing to the progress in mRNA delivery technology, especially with lipid nanoparticles (LNP). However, mRNA encapsulated-LNP (mRNA-LNP) cannot spontaneously cross the blood-brain barrier (BBB) which prevents the expression of foreign proteins in the brain. Microbubble-assisted focused ultrasound (FUS) BBB opening is an emerging technology that can transiently enhance BBB permeability. In this study, FUS/microbubble-assisted BBB opening was investigated for the intravenous delivery of mRNA-LNP to the brain. The intensity of FUS irradiation was optimized to 1.5 kW/cm(2), at which BBB opening occurred efficiently without hemorrhage or edema. Exogenous protein (luciferase) expression by mRNA-LNP, specifically at the FUS-irradiated side of the brain, occurred only when FUS and microbubbles were applied. This exogenous protein expression was faster but shorter than that of plasmid DNA delivery. Furthermore, foreign protein expression was observed in the microglia, along with CD31-positive endothelial cells, whereas no expression was observed in astrocytes or neurons. These results support the addition of mRNA-LNP to the lineup of nanoparticles delivered by BBB opening.