将细胞靶向分子和聚乙二醇（PEG）添加到纳米粒子（NP）药物输送系统中，是提高治疗药物的生物分布、特异性和摄取的标准方法。这些分子的空间表现形式通过局部配体浓度和PEG分子施加的立体阻碍作用之间的相互作用，部分影响着NP靶向细胞的亲和力。在此，我们展示了纳米粒子中的脂质相分离可以通过改变PEG和靶向蛋白分子在纳米粒子表面上的接近程度，来调节脂质体亲和力。利用脂质锚定的镍-三乙酸三胺（Ni-NTA）作为模型配体，我们证明将脂质锚定的Ni-NTA和PEG分子附着在不同的脂质区域中，可以通过增加配体聚集和减少立体阻碍，增强脂质体与癌细胞的结合。然后，我们使用这种技术来增强RGD修饰的脂质体的结合，这可以结合许多癌细胞上高表达的整合素。这些结果展示了脂质相分离的潜力，来调节脂质纳米载体上的靶向和屏蔽分子的空间表现形式，为增强NP药物输送系统的效力提供了有力工具。

The addition of both cell-targeting moieties and polyethylene glycol (PEG) to nanoparticle (NP) drug delivery systems is a standard approach to improve the biodistribution, specificity, and uptake of therapeutic cargo. The spatial presentation of these molecules affects avidity of the NP to target cells in part through an interplay between the local ligand concentration and the steric hindrance imposed by PEG molecules. Here, we show that lipid phase separation in nanoparticles can modulate liposome avidity by changing the proximity of PEG and targeting protein molecules on a nanoparticle surface. Using lipid-anchored nickel-nitrilotriacetic acid (Ni-NTA) as a model ligand, we demonstrate that the attachment of lipid anchored Ni-NTA and PEG molecules to distinct lipid domains in nanoparticles can enhance liposome binding to cancer cells by increasing ligand clustering and reducing steric hindrance. We then use this technique to enhance the binding of RGD-modified liposomes, which can bind to integrins overexpressed on many cancer cells. These results demonstrate the potential of lipid phase separation to modulate the spatial presentation of targeting and shielding molecules on lipid nanocarriers, offering a powerful tool to enhance the efficacy of NP drug delivery systems.