探索两亲分子结构对细胞内蛋白质传递能力的影响：二聚体与三聚体两亲分子,ACS Applied Materials & Interfaces

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探索两亲分子结构对细胞内蛋白质传递能力的影响：二聚体与三聚体两亲分子
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2023-05-23 , DOI: 10.1021/acsami.3c02198
Siying Chen ₁ , Zhicheng Le ₁ , Jiayue Gu ₁ , Lixin Liu ₁ , Zhijia Liu ₁ , Yongming Chen ₁

Affiliation

载体介导的细胞内蛋白质递送在生物学和医学中具有巨大的应用潜力。理想的载体应该是可控的和具有成本效益的，并且能够促进将不同类型的蛋白质稳健地递送到靶细胞中，从而确保在不同应用场景中的功效。在这里，我们描述了一种模块化化学方法，用于在一锅和温和条件下基于 Ugi 四组分反应生成小分子两亲分子库。然后，获得了两种不同类型的二聚体或三聚体结构的两亲物，用于通过体外细胞内蛋白质递送筛选试验。取决于两亲分子疏水尾部的精确调整，优化的三聚体两亲分子（TA）表现出更优异的蛋白质负载性能和更高的蛋白质通过内吞途径和随后的内体逃逸途径输送到细胞中的效率。此外，我们还证明了 TA 可能是一种通用的递送载体，能够将广谱蛋白质（尤其是难以递送的天然抗体）转运到胞质溶胶中。总的来说，我们描述了一个稳健的两亲平台，其设计明确且具有成本效益，可提高细胞溶质蛋白的递送能力，展示出开发基于细胞内蛋白的疗法的巨大希望。

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Exploring the Effect of Amphiphile Architecture on Intracellular Protein Delivery Capacity: Dimeric versus Trimeric Amphiphiles

Carrier-mediated intracellular protein delivery holds tremendous application potential in biology and medicine. The ideal carrier should be well-controlled and cost-effective and able to facilitate robust delivery of diverse types of proteins into the target cells, thus ensuring efficacy in different application scenarios. Here, we describe a modular chemistry approach for generating a small-molecule amphiphile molecular library based on the Ugi four-component reaction under one-pot and mild conditions. Then, two different types of amphiphiles with the dimeric or trimeric architecture were obtained for intracellular protein delivery through in vitro screening test. Depending on the precise adjustment of the hydrophobic tails of amphiphiles, the optimized trimeric amphiphile (TA) exhibited more superior protein loading performance and a higher efficiency of delivering proteins into cells through the endocytosis pathway and subsequent endosomal escape. Furthermore, we demonstrated that the TA could be a universal delivery carrier capable of transporting broad-spectrum proteins, especially for the hard-to-deliver native antibodies, into the cytosol. Overall, we describe a robust amphiphile platform with a well-defined and cost-effective design to improve the cytosolic protein delivery capacity, exhibiting great promise for developing intracellular protein-based therapeutics.

更新日期：2023-05-23

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