Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, TN 37996, USA.
School of Medical Laboratory Science, University of Tennessee Medical Center, Knoxville, TN 37996, USA.
J Control Release. 2024 Feb;366:282-296. doi: 10.1016/j.jconrel.2023.12.019. Epub 2024 Jan 5.
Poly-ethylene-glycol (PEG)-based nanoparticles (NPs) - including cylindrical micelles (CNPs), spherical micelles (SNPs), and PEGylated liposomes (PLs) - are hypothesized to be cleared in vivo by opsonization followed by liver macrophage phagocytosis. This hypothesis has been used to explain the rapid and significant localization of NPs to the liver after administration into the mammalian vasculature. Here, we show that the opsonization-phagocytosis nexus is not the major factor driving PEG-NP - macrophage interactions. First, mouse and human blood proteins had insignificant affinity for PEG-NPs. Second, PEG-NPs bound macrophages in the absence of serum proteins. Third, lipoproteins blocked PEG-NP binding to macrophages. Because of these findings, we tested the postulate that PEG-NPs bind (apo)lipoprotein receptors. Indeed, PEG-NPs triggered an in vitro macrophage transcription program that was similar to that triggered by lipoproteins and different from that triggered by lipopolysaccharide (LPS) and group A Streptococcus. Unlike LPS and pathogens, PLs did not increase transcripts involved in phagocytosis or inflammation. High-density lipoprotein (HDL) and SNPs triggered remarkably similar mouse bone-marrow-derived macrophage transcription programs. Unlike opsonized pathogens, CNPs, SNPs, and PLs lowered macrophage autophagosome levels and either reduced or did not increase the secretion of key macrophage pro-inflammatory cytokines and chemokines. Thus, the sequential opsonization and phagocytosis process is likely a minor aspect of PEG-NP - macrophage interactions. Instead, PEG-NP interactions with (apo)lipoprotein and scavenger receptors appear to be a strong driving force for PEG-NP - macrophage binding, entry, and downstream effects. We hypothesize that the high presence of these receptors on liver macrophages and on liver sinusoidal endothelial cells is the reason PEG-NPs localize rapidly and strongly to the liver.
聚乙二醇（PEG）基纳米颗粒（NPs） - 包括圆柱形胶束（CNPs）、球形胶束（SNPs）和 PEG 化脂质体（PLs） - 据推测在体内通过调理作用后被肝巨噬细胞吞噬清除。这一假说被用来解释 NP 在给药进入哺乳动物血管系统后迅速而显著地定位到肝脏。在这里，我们表明调理吞噬作用连接体不是驱动 PEG-NP-巨噬细胞相互作用的主要因素。首先，小鼠和人血液蛋白对 PEG-NP 没有明显的亲和力。其次，PEG-NP 在没有血清蛋白的情况下与巨噬细胞结合。第三，脂蛋白阻止 PEG-NP 与巨噬细胞结合。由于这些发现，我们测试了 PEG-NP 结合（载脂蛋白）受体的假设。事实上，PEG-NP 触发了一种体外巨噬细胞转录程序，类似于脂蛋白触发的转录程序，与脂多糖（LPS）和 A 组链球菌触发的转录程序不同。与 LPS 和病原体不同，PLs 不会增加参与吞噬或炎症的转录物。高密度脂蛋白（HDL）和 SNPs 触发了非常相似的小鼠骨髓来源的巨噬细胞转录程序。与调理后的病原体不同，CNPs、SNPs 和 PLs 降低了巨噬细胞自噬体水平，并降低或不增加关键巨噬细胞前炎症细胞因子和趋化因子的分泌。因此，调理作用和吞噬作用的顺序过程可能是 PEG-NP-巨噬细胞相互作用的一个次要方面。相反，PEG-NP 与（载脂蛋白）和清道夫受体的相互作用似乎是 PEG-NP-巨噬细胞结合、进入和下游效应的强大驱动力。我们假设这些受体在肝巨噬细胞和肝窦内皮细胞上的高表达是 PEG-NPs 迅速而强烈地定位到肝脏的原因。
