文獻(xiàn)：血清熱滅活降低 ApoE 介導(dǎo)的 D-Lin-MC3-DMA 脂質(zhì)納米顆粒的攝取

鏈接：https://www.beilstein-journals.org/bjnano/articles/16/57

作者：德米安·范斯特拉滕， 盧克·范德·謝波普， 羅文·弗朗特， 彼得·維德和 雷蒙德·M·希弗勒斯

節(jié)選：

抽象的

納米粒子在藥物遞送研究中發(fā)揮著至關(guān)重要的作用。納米粒子給藥后在其表面形成的蛋白質(zhì)冠因其對其性能的顯著影響而備受關(guān)注。脂質(zhì)納米粒子 (LNP) 依賴蛋白質(zhì)冠的形成來實(shí)現(xiàn)其靶向性。此類蛋白質(zhì)-納米粒子相互作用通常*初使用體外細(xì)胞模型進(jìn)行研究，旨在*終了解 LNP 在體內(nèi)的生物分布和載藥遞送效率。在體外細(xì)胞培養(yǎng)中，通常會(huì)在培養(yǎng)基中添加胎牛血清 (FCS) 以提供營養(yǎng)并促進(jìn)細(xì)胞活力和生長。通常對 FCS 進(jìn)行熱滅活以防止補(bǔ)體系統(tǒng)激活。然而，該過程對蛋白質(zhì)冠形成以及進(jìn)而對 LNP 功能的影響尚不清楚。本文，我們研究了血清熱滅活對含有 D-lin-MC3-DMA (MC3) 或 C12-200 (C12) 可電離脂質(zhì)的 LNP 中蛋白質(zhì)冠形成的影響。在含有未處理或熱滅活血清的培養(yǎng)基中，測定了LNP的細(xì)胞攝取和siRNA遞送效率。從機(jī)制上講，我們發(fā)現(xiàn)載脂蛋白E（一種對MC3 LNP趨向性至關(guān)重要的蛋白冠成分）在FCS熱滅活后穩(wěn)定性和功能性降低，從而對MC3 LNP的攝取和貨物遞送產(chǎn)生負(fù)面影響，但對C12 LNP則無影響。我們的研究結(jié)果強(qiáng)調(diào)了體外實(shí)驗(yàn)中被忽視的因素的重要性，這些因素可能會(huì)無意中影響LNP的性能。這些發(fā)現(xiàn)有助于改進(jìn)體外研究蛋白冠形成的方案，并防止LNP開發(fā)中的偏差。

Abstract

Nanoparticles play a crucial role in drug delivery research. The protein corona that develops on the surface of nanoparticles after administration has garnered substantial attention due to the significant effects it has on their performance. Lipid nanoparticles (LNPs) depend on protein corona formation to mediate their targeting. Such protein–nanoparticle interactions are often initially studied using in vitro cellular models aiming to eventually understand biodistribution and cargo delivery efficiency of the LNPs in vivo. For in vitro cell culture, fetal calf serum (FCS) is supplemented to culture media to provide nutrients and promote cell viability and growth. Heat inactivation of FCS is often performed to prevent complement system activation. However, the effect of this process on protein corona formation and, in turn, LNP functionality is unclear. Here, we investigated the effects of serum heat inactivation on protein corona formation on LNPs containing D-lin-MC3-DMA (MC3) or C12-200 (C12) ionizable lipids. Cellular uptake and siRNA delivery efficiency of the LNPs were determined in media containing untreated or heat-inactivated serum. Mechanistically, we found that apolipoprotein E, a protein corona component that is crucial for MC3 LNP tropism, displayed reduced stability and functionality upon heat inactivation of FCS, thereby negatively influencing uptake and cargo delivery of MC3 LNPs, but not C12 LNPs. Our results underline the importance of overlooked factors in in vitro experiments that can inadvertently affect LNP performance. These findings can help to improve protocols to study protein corona formation in vitro and prevent bias in LNP development.

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