A Membrane-Embedded Macromolecular Catalyst with Substrate Selectivity in Live Cells
A Membrane-Embedded Macromolecular Catalyst with Substrate Selectivity in Live Cells
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一种在活细胞中具有底物选择性的膜嵌入高分子催化剂
DOI：
10.1021/jacs.2c11168
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发表时间：
2022-12-16
影响因子：
15
通讯作者：
Bai, Yugang
中科院分区：
文献类型：
--
作者：
Deng, Yingjiao;Wu, Tong;Bai, Yugang
底物选择性是天然酶的“结合-催化”工作流程中最具吸引力的特征之一，因此是开发介导非生物转化的合成酶模拟物的目标。然而，尽管最近成功地制备了基于单链纳米颗粒的底物选择性酶模拟物，但将这种选择性扩展到生命系统中的例子还没有。在这篇文章中，我们报告了基于阳离子密壳纳米颗粒（DSNP）支架的酶模拟大分子催化剂的细胞内底物选择性。通过对DSNP的结构-活性关系的系统研究，我们证明了DSNP具有优异的膜亲和性，其受几个影响因素的影响，即电荷密度、电荷类型和颗粒尺寸，并且表现最好的富磷DSNP可以用作膜嵌入催化剂（MEC）用于有效的膜上合成。重要的是，DSNP催化剂在用作膜上连接的MEC时保持其对亲脂性和阴离子底物的选择性。这种底物选择性和膜上催化策略的有用性用具有低细胞渗透性和阴离子性质的几种感兴趣的分子来举例说明，这些分子在它们直接在细胞膜上形成后被成功地转运到真核细胞中。
Substrate selectivity is one of the most attractive features of natural enzymes from their "bind-to-catalyze" working flow and is thus a goal for the development of synthetic enzyme mimics that mediate abiotic transformations. However, despite the recent success in the preparation of substrate-selective enzyme mimics based on single-chain nanoparticles, examples extending such selectivity into living systems have been absent. In this article, we report the in cellulo substrate selectivity of an enzyme-mimicking macromolecular catalyst based on a cationic dense-shell nanoparticle (DSNP) scaffold. With a systematic study on DSNP's structure- activity relationship, we demonstrate that the DSNP has excellent membrane affinity that is governed by several contributing factors, namely, charge density, type of charge, and particle size, and the best-performing phosphonium-rich DSNP can be used as a membrane-embedded catalyst (MEC) for efficient on-membrane synthesis. Importantly, the DSNP catalyst retains its selectivity toward lipophilic and anionic substrates when working as an MEC for on-membrane ligation. The usefulness of such substrate selectivity and on-membrane catalysis strategy was exemplified with several molecules of interest with low cell permeability and anionic nature, which were successfully transported into eukaryotic cells by after their formation directly on the cell membrane.