Department of Nanomedicine and Drug Targeting, Groningen Research Institute of Pharmacy, University of Groningen, A. Deusinglaan 1, 9713AV Groningen, The Netherlands.
Nano Lett. 2022 Apr 13;22(7):3118-3124. doi: 10.1021/acs.nanolett.2c00537. Epub 2022 Apr 4.
Nanosized drug carriers enter cells via active mechanisms of endocytosis but the pathways involved are often not clarified. Cells possess several mechanisms to generate membrane curvature during uptake. However, the mechanisms of membrane curvature generation for nanoparticle uptake have not been explored so far. Here, we combined different methods to characterize how silica nanoparticles with a human serum corona enter cells. In these conditions, silica nanoparticles are internalized via the LDL receptor (LDLR). We demonstrate that despite the interaction with LDLR, uptake is not clathrin-mediated, as usually observed for this receptor. Additionally, silencing the expression of different proteins involved in clathrin-independent mechanisms and several BAR-domain proteins known to generate membrane curvature strongly reduces nanoparticle uptake. Thus, nanosized objects targeted to specific receptors, such as here LDLR, can enter cells via different mechanisms than their endogenous ligands. Additionally, nanoparticles may trigger alternative mechanisms of membrane curvature generation for their internalization.
纳米药物载体通过细胞内吞的主动机制进入细胞，但所涉及的途径通常并不明确。细胞在摄取过程中拥有几种产生膜曲率的机制。然而，目前尚未探索纳米颗粒摄取过程中产生膜曲率的机制。在这里，我们结合了不同的方法来描述带有人类血清蛋白冠的二氧化硅纳米颗粒进入细胞的方式。在这些条件下，二氧化硅纳米颗粒通过 LDL 受体（LDLR）被内化。我们证明，尽管与 LDLR 相互作用，但摄取不是网格蛋白介导的，因为通常观察到该受体是这样的。此外，沉默参与网格蛋白非依赖性机制的不同蛋白和几种已知能产生膜曲率的 BAR 结构域蛋白的表达，强烈降低了纳米颗粒的摄取。因此，靶向特定受体（如 LDLR）的纳米尺寸物体可以通过与其内源性配体不同的机制进入细胞。此外，纳米颗粒可能会触发用于其内化的替代膜曲率产生机制。
