Understanding how cells process nanoparticles is crucial to optimize nanomedicine efficacy. However, characterizing cellular pathways is challenging, especially if non-canonical mechanisms are involved. In this Article a genome-wide forward genetic screening based on insertional mutagenesis is applied to discover receptors and proteins involved in the intracellular accumulation (uptake and intracellular processing) of silica nanoparticles. The nanoparticles are covered by a human serum corona known to target the low-density lipoprotein receptor (LDLR). By sorting cells with reduced nanoparticle accumulation and deep sequencing after each sorting, 80 enriched genes are identified. We find that, as well as LDLR, the scavenger receptor SCARB1 also mediates nanoparticle accumulation. Additionally, heparan sulfate acts as a specific nanoparticle receptor, and its role varies depending on cell and nanoparticle type. Furthermore, some of the identified targets affect nanoparticle trafficking to the lysosomes. These results show the potential of genetic screening to characterize nanoparticle pathways. Additionally, they indicate that corona-coated nanoparticles are internalized via multiple receptors.

了解细胞如何处理纳米粒子对于优化纳米医学功效至关重要。然而，表征细胞途径具有挑战性，特别是如果涉及非典型机制。在本文中，基于插入诱变的全基因组正向遗传筛选用于发现参与二氧化硅纳米颗粒细胞内积累（摄取和细胞内加工）的受体和蛋白质。纳米颗粒被人血清冠层覆盖，已知该血清冠层以低密度脂蛋白受体（LDLR）为目标。通过对纳米颗粒积累减少的细胞进行分选，并在每次分选后进行深度测序，鉴定出 80 个富集基因。我们发现，除了 LDLR 之外，清道夫受体 SCARB1 也介导纳米颗粒的积累。此外，硫酸乙酰肝素充当特定的纳米颗粒受体，其作用根据细胞和纳米颗粒类型而变化。此外，一些已确定的目标会影响纳米颗粒向溶酶体的运输。这些结果显示了遗传筛选表征纳米颗粒途径的潜力。此外，他们表明电晕涂层纳米粒子通过多个受体内化。