DMG-PEG2000一种不稳定 PEG-脂质的脂质纳米颗粒

链接：https://xueshu.baidu.com/usercenter/paper/show?paperid=111h0820k42y0re09m0a06a0rh159218&site=xueshu_se

作者：Camilla Hald Gregersen]; Razan Mearraoui; Pia Pernille Søgaard; Gael Clergeaud; Karsten Petersson; Andrew J. Urquhart; Jens B. Simonsen

Nucleic acid-based therapeutics encapsulated into lipid nanoparticles (LNPs) can potentially target the root cause of genetic skin diseases . Although nanoparticles are considered impermeable to skin, research and clinical studies have shown that nanoparticles can penetrate into skin with reduced skin barrier function when administered topically.Studies have shown that epidermal keratinocytes express the low-density lipoprotein receptor (LDLR) that mediates endocytosis of apolipoprotein E (apoE)-associated nanoparticles and that dermal fibroblasts express mannose receptors. Here we prepared LNPs designed to exploit these different endocytic pathways for intracellular mRNA delivery to the two most abundant skin cell types, containing: (i) labile PEG-lipids (DMG-PEG2000) prone to dissociate and facilitate apoE-binding to LNPs, enabling apoE-LDLR mediated uptake in keratinocytes , (ii) non-labile PEG-lipids (DSPE-PEG2000) to impose stealth-like properties to LNPs to enable targeting of distant cells, and (iii) mannose-conjugated PEG-lipids (DSPE-PEG2000-Mannose) to target fibroblasts or potentially immune cells containing mannose receptors . All types of LNPs were prepared by vortex mixing and formed monodisperse (PDI ∼ 0.1) LNP samples with sizes of 130 nm (±25%) and high mRNA encapsulation efficiencies (≥90%). The LNP-mediated transfection potency in keratinocytes and fibroblasts was highest for LNPs containing labile PEG-lipids, with the addition of apoE greatly enhancing transfection via LDLR. Coating LNPs with mannose did not improve transfection, and stealth-like LNPs show limited to no transfection.Taken together, our studies suggest using labile PEG-lipids and co-administration of apoE when exploring LNPs for skin delivery.

译文：

封装在脂质纳米颗粒（LNPs）中的基于核酸的疗法可能会针对遗传性皮肤病的根本原因。尽管纳米颗粒被认为是皮肤不可渗透的，但研究和临床研究表明，当局部给药时，纳米颗粒可以渗透到皮肤中，但皮肤屏障功能会降低。研究表明，表皮角质形成细胞表达低密度脂蛋白受体（LDLR），该受体介导载脂蛋白E（apoE）相关纳米颗粒的内吞作用，皮肤成纤维细胞表达甘露糖受体。在这里，我们制备了LNPs，旨在利用这些不同的内吞途径将细胞内mRNA递送到两种*丰富的皮肤细胞类型，其中含有：（i）易解离并促进apoE与LNPs结合的不稳定PEG脂质（DMG-PEG2000），使apoE LDLR介导的角质形成细胞摄取成为可能。所有类型的LNP都是通过涡流混合制备的，形成了单分散（PDI∼0.1）LNP样品，尺寸为130 nm（±25%），mRNA包封效率高（≥90%）。对于含有不稳定PEG脂质的LNP，LNP介导的角质形成细胞和成纤维细胞转染效力*高，添加apoE大大增强了LDLR的转染。用甘露糖涂覆LNPs并不能提高转染率，隐形LNPs显示仅限于无转染。总的来说，我们的研究建议在探索LNPs用于皮肤递送时使用不稳定的PEG脂质和apoE的联合给药。

DOI：10.1016/j.ejpb.2024.114219

出处：《European Journal of Pharmaceutics & Biopharmaceutics》

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