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首页> 外文期刊>Biomaterials Science >Helper lipid structure influences protein adsorption and delivery of lipid nanoparticles to spleen and liver
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Helper lipid structure influences protein adsorption and delivery of lipid nanoparticles to spleen and liver

机译：辅助脂质结构影响蛋白质吸附和脂质纳米颗粒的脂肪纳米粒子递送至脾脏和肝脏

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摘要

Nucleic acids, such as messenger RNAs, antisense oligonucleotides, and short interfering RNAs, hold great promise for treating previously 'undruggable' diseases. However, there are numerous biological barriers that hinder nucleic acid delivery to target cells and tissues. While lipid nanoparticles (LNPs) have been developed to protect nucleic acids from degradation and mediate their intracellular delivery, it is challenging to predict how alterations in LNP formulation parameters influence delivery to different organs. In this study, we utilized high-throughput in vivo screening to probe for structure-function relationships of intravenously administered LNPs along with quartz crystal microbalance with dissipation monitoring (QCM-D) to measure the binding affinity of LNPs to apolipoprotein E (ApoE), a protein implicated in the clearance and uptake of lipoproteins by the liver. High-throughput in vivo screening of a library consisting of 96 LNPs identified several formulations containing the helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) that preferentially accumulated in the liver, while identical LNPs that substituted DOPE with the helper lipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) preferentially accumulated in the spleen. Using QCM-D, it was found that one DOPE-containing LNP formulation (LNP 42) had stronger interactions with ApoE than an identical LNP formulation that substituted DOPE with DSPC (LNP 90). In order to further validate our findings, we formulated LNP 42 and LNP 90 to encapsulate Cy3-siRNA or mRNA encoding for firefly luciferase. The DSPC-containing LNP (LNP 90) was found to increase delivery to the spleen for both siRNA (two-fold) and mRNA (five-fold). In terms of liver delivery, the DOPE-containing LNP (LNP 42) enhanced mRNA delivery to the liver by two-fold and improved liver transfection by three-fold. Understanding the role of the helper lipid in LNP biodistribution and ApoE adsorption may aid in the future design of LNPs for nucleic acid therapeutics.
机译：核酸，如信使RNA，反义寡核苷酸和短暂干扰RNA，对治疗以前的“不可驾湿的”疾病具有很大的承担。然而，存在许多生物屏障，可使核酸输送给靶细胞和组织。虽然已经开发了脂质纳米颗粒（LNP）以保护核酸免于降解并介导细胞内递送，但预测LNP配方参数的改变是挑战性的，可以影响输送到不同器官。在本研究中，我们利用体内筛选的高通量对静脉内施用的LNP的结构功能关系探讨，以及用耗散监测（QCM-D）的石英晶微观，以测量LNP与载脂蛋白E（Apoe）的结合亲和力，一种蛋白质，肝脏含有脂蛋白的间隙和吸收。 Vivo筛选的高通量包括96Lnps的文库，鉴定了含有优先在肝脏中积累的辅助脂质1,2-dioleyoyl-sn-甘油-3-磷乙醇胺（掺杂）的若干制剂，而相同的LNP被取代的掺杂剂辅助脂质1,2- Distearoyl-Sn-甘油-3-磷光啉（DSPC）优先积聚在脾脏中。使用QCM-D，发现含有一种含有的LNP制剂（LNP 42）与帕多伊的相互作用具有较强的相互作用，而不是与DSPC（LNP 90）取代的相同的LNP制剂。为了进一步验证我们的发现，我们配制了LNP 42和LNP 90，以包封用于萤火虫荧光素酶的Cy3-siRNA或mRNA编码。发现含DSPC的LNP（LNP 90）将输送到SiRNA（双倍）和mRNA（五倍）的脾脏增加。就肝脏递送而言，含掺杂剂的LNP（LNP 42）通过双倍和改善肝脏转染的肝脏增强mRNA递送至肝脏。理解辅助脂质在LNP生物分布和Apoe吸附中的作用可能有助于未来LNP的核酸治疗剂的设计。

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