计算辅助设计的可电离胆固醇脂质纳米颗粒调节肝脏mRNA积累。

IF 15.6 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Yilong Teng,Yuxuan Guo,Zhixiang Liu,Maoping Tang,William Stewart,Xiaoyang Xu,Xue-Qing Zhang
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引用次数: 0

摘要

mRNA疗法正在成为一种革命性的治疗方式,为治疗和预防广泛的疾病提供了一个通用的平台。基于非病毒纳米颗粒的递送系统,特别是脂质纳米颗粒(LNPs),对于其成功的临床转化至关重要。然而,目前fda批准的四组分脂质纳米颗粒(LNP)制剂主要在肝脏中积累,这是由于载脂蛋白E/低密度脂蛋白受体(ApoE/LDLR)在全身给药后被肝细胞吸收,这极大地限制了肝外mRNA的传递并限制了其更广泛的治疗应用。在此,我们提出了一种计算辅助设计方法来识别和优化具有肝外递送特性的可电离胆固醇(iChol)脂质,同时制定了一个三组分LNP系统。利用diffdock - l辅助设计,我们合理地将LNPs的两个关键成分,胆固醇和可电离脂质整合为一个单一的化学实体,并开发了一类新型的可电离胆固醇(iChol)脂质,其与ApoE的相互作用减弱。这些脂质与磷脂和聚乙二醇化脂质一起,可以自组装成稳定的三组分脂质纳米颗粒(Tc-LNPs)。与传统的四组分LNP相比,tc -LNP对ApoE的吸附减少。重要的是,与市售LNPs相比,Tc-LNPs通过调节ApoE/ ldlr介导的肝细胞内吞作用减少了肝脏积聚,并改善了脾脏富集。此外,该方法也适用于其他可电离脂质,包括市售的ALC-0315脂质,为加速肝外输送LNPs的发展铺平了新的道路,并有可能扩大基于mrna的治疗方法的应用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Computationally Aided Design of Ionizable Cholesteryl Lipids for Lipid Nanoparticles to Modulate Hepatic mRNA Accumulation.
mRNA therapeutics are emerging as a revolutionary therapeutic modality, providing a versatile platform for the treatment and prevention of a broad spectrum of diseases. Nonviral nanoparticle-based delivery systems, particularly lipid nanoparticles (LNPs), are essential for their successful clinical translation. However, the currently FDA-approved four-component lipid nanoparticle (LNP) formulations primarily accumulate in the liver due to apolipoprotein E/Low-Density Lipoprotein Receptor (ApoE/LDLR)-mediated uptake by hepatic cells following systemic administration, which significantly limits extrahepatic mRNA delivery and restricts its broader therapeutic applications. Herein, we present a computationally assisted design approach to identify and optimize ionizable cholesteryl (iChol) lipids with extrahepatic delivery properties while formulating a three-component LNP system. Using DiffDock-L-assisted design, we rationally integrated two key components of LNPs, cholesterol and ionizable lipid, into a single chemical entity and developed a novel class of ionizable cholesteryl (iChol) lipids that exhibit attenuated interactions with ApoE. These iChol lipids, along with phospholipids and PEGylated lipids, can self-assemble into stable three-component lipid nanoparticles (Tc-LNPs). The Tc-LNPs exhibit decreased ApoE adsorption compared to conventional four-component LNP counterparts. Importantly, the Tc-LNPs show reduced hepatic accumulation via modulating ApoE/LDLR-mediated endocytosis in hepatocytes and improved spleen enrichment compared to commercially available LNPs. Additionally, this approach is applicable to other ionizable lipids, including the commercially available ALC-0315 lipid, paving a new way for accelerating the development of extrahepatic delivery LNPs and potentially expanding the applications of mRNA-based therapeutics.
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来源期刊
CiteScore
24.40
自引率
6.00%
发文量
2398
审稿时长
1.6 months
期刊介绍: The flagship journal of the American Chemical Society, known as the Journal of the American Chemical Society (JACS), has been a prestigious publication since its establishment in 1879. It holds a preeminent position in the field of chemistry and related interdisciplinary sciences. JACS is committed to disseminating cutting-edge research papers, covering a wide range of topics, and encompasses approximately 19,000 pages of Articles, Communications, and Perspectives annually. With a weekly publication frequency, JACS plays a vital role in advancing the field of chemistry by providing essential research.
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