HIV-1 模拟聚合物纳米颗粒的硬度调节神经节苷脂介导的细胞摄取和运输,Advanced Science

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HIV-1 模拟聚合物纳米颗粒的硬度调节神经节苷脂介导的细胞摄取和运输
Advanced Science ( IF 14.3 ) Pub Date : 2020-07-29 , DOI: 10.1002/advs.202000649
Behnaz Eshaghi ₁ , Nourin Alsharif ₂ , Xingda An ₁ , Hisashi Akiyama ₃ , Keith A Brown ₂ , Suryaram Gummuluru ₃ , Björn M Reinhard ₁

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单唾液酸二己糖神经节苷脂 GM3 及其与 CD169 (Siglec-1) 的结合已被证明是人类免疫缺陷病毒 1 (HIV-1) 在髓系细胞中含病毒区室 (VCC) 中与糖蛋白无关的隔离的关键因素。在这里，脂质包裹的聚合物纳米颗粒 (NP) 被用作病毒模拟模型，以表征核心硬度对巨噬细胞中 GM3-CD169 结合触发的 NP 摄取和细胞内命运的影响。GM3 功能化脂质包裹的纳米颗粒由聚乳酸乙醇酸(PLGA) 以及低分子量和高分子量聚乳酸（PLA ^lMW和 PLA ^hMW）核心组装而成。纳米粒子的平均直径为 146 ± 17 nm，并且具有由自组装脂质层定义的可比较的表面特性。由于玻璃化转变温度的差异，生理条件下 PLGA ( E _PLGA = 60 ± 32 MPa)、PLA ^lMW ( E _PLA^lMW = 86 ± 25 MPa) 和 PLA ^{hMW (}E ) 之间的杨氏模量( E ) 有很大差异。_PLA^hMW = 1.41 ± 0.67 GPa) 纳米粒子。只有僵硬的 GM3 呈递 PLA ^hMW NP，而不是较软的 PLGA 或 PLA ^lMW NP，可以避免溶酶体途径并定位于类似于 VCC 的四跨膜蛋白 (CD9) 阳性区室中。这些观察结果表明，GM3-CD169 诱导的纳米颗粒在非溶酶体区室中的隔离并不完全由配体-受体相互作用决定，还取决于核心硬度。

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Stiffness of HIV‐1 Mimicking Polymer Nanoparticles Modulates Ganglioside‐Mediated Cellular Uptake and Trafficking

The monosialodihexosylganglioside, GM3, and its binding to CD169 (Siglec‐1) have been indicated as key factors in the glycoprotein‐independent sequestration of the human immunodeficiency virus‐1 (HIV‐1) in virus‐containing compartments (VCCs) in myeloid cells. Here, lipid‐wrapped polymer nanoparticles (NPs) are applied as a virus‐mimicking model to characterize the effect of core stiffness on NP uptake and intracellular fate triggered by GM3‐CD169 binding in macrophages. GM3‐functionalized lipid‐wrapped NPs are assembled with poly(lactic‐co‐glycolic) acid (PLGA) as well as with low and high molecular weight polylactic acid (PLA^lMW and PLA^hMW) cores. The NPs have an average diameter of 146 ± 17 nm and comparable surface properties defined by the self‐assembled lipid layer. Due to differences in the glass transition temperature, the Young's modulus (E) differs substantially under physiological conditions between PLGA (E_PLGA = 60 ± 32 MPa), PLA^lMW (E_PLA^lMW = 86 ± 25 MPa), and PLA^hMW (E_PLA^hMW = 1.41 ± 0.67 GPa) NPs. Only the stiff GM3‐presenting PLA^hMW NPs but not the softer PLGA or PLA^lMW NPs avoid a lysosomal pathway and localize in tetraspanin (CD9)‐positive compartments that resemble VCCs. These observations suggest that GM3‐CD169‐induced sequestration of NPs in nonlysosomal compartments is not entirely determined by ligand–receptor interactions but also depends on core stiffness.

更新日期：2020-09-23

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