Impact of Lipid Tail Length on the Organ Selectivity of mRNA-Lipid Nanoparticles.

IF 9.6 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Nano Letters Pub Date : 2024-10-07 DOI:10.1021/acs.nanolett.4c02566

Kazuki Hashiba, Masamitsu Taguchi, Sachiko Sakamoto, Ayaka Otsu, Yoshiki Maeda, Yuichi Suzuki, Hirofumi Ebe, Arimichi Okazaki, Hideyoshi Harashima, Yusuke Sato

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Abstract

The delivery of mRNA molecules to organs beyond the liver is valuable for therapeutic applications. Functionalized lipid nanoparticles (LNPs) using exogenous mechanisms can regulate in vivo mRNA expression profiles from hepatocytes to extrahepatic tissues but lead to process complexity and cost escalation. Here, we report that mRNA expression gradually shifts from the liver to the spleen in an ionizable lipid tail length-dependent manner. Remarkably, this simple chemical strategy held true even when different ionizable lipid head structures were employed. As a potential mechanism underlying this discovery, our data suggest that 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) is enriched on the surface of mRNA/LNPs with short-tail lipids. This feature limits their interaction with biological components, avoiding their rapid hepatic clearance. We also show that spleen-targeting LNPs loaded with SARS-CoV-2 receptor-binding domain (RBD) mRNA can efficiently induce immune responses and neutralize activity following intramuscular vaccination priming and boosting.

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脂质尾部长度对 mRNA 脂质纳米颗粒器官选择性的影响

将 mRNA 分子输送到肝脏以外的器官具有重要的治疗应用价值。利用外源机制的功能化脂质纳米颗粒（LNPs）可以调节肝细胞到肝外组织的体内 mRNA 表达谱，但会导致过程复杂和成本上升。在这里，我们报告了 mRNA 表达以可电离脂质尾长度依赖的方式从肝脏逐渐转移到脾脏。值得注意的是，即使采用不同的可电离脂质头部结构，这种简单的化学策略也能保持不变。作为这一发现的潜在机制，我们的数据表明，1,2-二硬脂酰-sn-甘油-3-磷酸胆碱（DSPC）富集在具有短尾脂质的 mRNA/LNPs 表面。这一特点限制了它们与生物成分的相互作用，避免了它们被肝脏快速清除。我们的研究还表明，装载有 SARS-CoV-2 受体结合域 (RBD) mRNA 的脾脏靶向 LNPs 可在肌肉注射疫苗起效和增强后有效诱导免疫反应和中和活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nano Letters 工程技术-材料科学：综合

CiteScore

16.80

自引率

2.80%

发文量

1182

审稿时长

1.4 months

期刊介绍： Nano Letters serves as a dynamic platform for promptly disseminating original results in fundamental, applied, and emerging research across all facets of nanoscience and nanotechnology. A pivotal criterion for inclusion within Nano Letters is the convergence of at least two different areas or disciplines, ensuring a rich interdisciplinary scope. The journal is dedicated to fostering exploration in diverse areas, including: - Experimental and theoretical findings on physical, chemical, and biological phenomena at the nanoscale - Synthesis, characterization, and processing of organic, inorganic, polymer, and hybrid nanomaterials through physical, chemical, and biological methodologies - Modeling and simulation of synthetic, assembly, and interaction processes - Realization of integrated nanostructures and nano-engineered devices exhibiting advanced performance - Applications of nanoscale materials in living and environmental systems Nano Letters is committed to advancing and showcasing groundbreaking research that intersects various domains, fostering innovation and collaboration in the ever-evolving field of nanoscience and nanotechnology.