DMG-PEG2000一種不穩(wěn)定 PEG-脂質(zhì)的脂質(zhì)納米顆粒

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

作者：Camilla Hald Gregersen]; Razan Mearraoui; Pia Pernille S?gaard; 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.

譯文：

封裝在脂質(zhì)納米顆粒（LNPs）中的基于核酸的療法可能會針對遺傳性皮膚病的根本原因。盡管納米顆粒被認(rèn)為是皮膚不可滲透的，但研究和臨床研究表明，當(dāng)局部給藥時，納米顆�？梢詽B透到皮膚中，但皮膚屏障功能會降低。研究表明，表皮角質(zhì)形成細(xì)胞表達(dá)低密度脂蛋白受體（LDLR），該受體介導(dǎo)載脂蛋白E（apoE）相關(guān)納米顆粒的內(nèi)吞作用，皮膚成纖維細(xì)胞表達(dá)甘露糖受體。在這里，我們制備了LNPs，旨在利用這些不同的內(nèi)吞途徑將細(xì)胞內(nèi)mRNA遞送到兩種*豐富的皮膚細(xì)胞類型，其中含有：（i）易解離并促進(jìn)apoE與LNPs結(jié)合的不穩(wěn)定PEG脂質(zhì)（DMG-PEG2000），使apoE LDLR介導(dǎo)的角質(zhì)形成細(xì)胞攝取成為可能。所有類型的LNP都是通過渦流混合制備的，形成了單分散（PDI～0.1）LNP樣品，尺寸為130 nm（±25%），mRNA包封效率高（≥90%）。對于含有不穩(wěn)定PEG脂質(zhì)的LNP，LNP介導(dǎo)的角質(zhì)形成細(xì)胞和成纖維細(xì)胞轉(zhuǎn)染效力*高，添加apoE大大增強(qiáng)了LDLR的轉(zhuǎn)染。用甘露糖涂覆LNPs并不能提高轉(zhuǎn)染率，隱形LNPs顯示僅限于無轉(zhuǎn)染�？偟膩碚f，我們的研究建議在探索LNPs用于皮膚遞送時使用不穩(wěn)定的PEG脂質(zhì)和apoE的聯(lián)合給藥。

DOI：10.1016/j.ejpb.2024.114219

出處：《European Journal of Pharmaceutics & Biopharmaceutics》

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