Being driven by non-covalent interactions, the formation of functional assemblies (or aggregates) of small molecules at nanoscale is a more common process in water than one would think. While most efforts on self-assembly in cellular environment concentrate on the assemblies of proteins (e.g., microtubules or amyloid fibers), nanoscale assemblies of small molecules are emerging functional entities that exhibit important biological function in cellular environments. This review describes the increasing efforts on the exploration of nanoscale assemblies of small molecules that largely originate from the serendipitous observations in research fields other than nanoscience and technology. Specifically, we describe that nanoscale assemblies of small molecules exhibit unique biological functions in extracellular and intracellular environment, thus inducing various cellular responses, like causing cell death or promoting cell proliferation. We first survey certain common feature of nanoscale molecular assemblies, then discuss several specific examples, such as, nanoscale assemblies of small peptides accumulated in the cells for selectively inhibiting cancer cells via promiscuous interactions with proteins, and nanoscale assemblies of a glycoconjugate for promoting the proliferation of stem cells or for suppressing immune responses. Subsequently, we emphasize the spatiotemporal control of nanoscale assemblies for controlling the cell fate, particularly illustrate a paradigm-shifting approach-enzyme-instructed self-assembly (EISA), that is, the integration of enzymatic reaction and self-assembly-for generating nanoscale assemblies from innocuous monomers for selectively inhibiting cancer cells. Moreover, we introduce a convenient assay for proteomic study of the proteins that interact with nanoscale assemblies of small molecules in cellular environment. Furthermore, we introduce the use of ligand-receptor interaction to catalyze the formation of nanoscale assemblies. By illustrating these experimental strategies for controlling the formation of nanoscale assemblies of small molecules and for identifying their corresponding protein targets, we aim to highlight that, though not being defined at the genetic level, nanoscale assemblies of small molecules are able to perform many critical biological functions. We envision that nanoscale assemblies of small molecules are a new frontier at the intersection of nanoscience and cell biology and biomedicine. In addition, we discuss the challenges and perspectives of relevant potential biomedical applications of nanoscale assemblies of small molecules.

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小分子的纳米级组装控制细胞的命运

在非共价相互作用的驱动下，纳米级小分子功能组装（或聚集体）的形成是水中比人们想象的更常见的过程。虽然细胞环境中自组装的大多数努力集中在蛋白质（例如微管或淀粉样纤维）的组装上，但小分子的纳米级组装是新兴的功能实体，在细胞环境中表现出重要的生物功能。这篇综述描述了对小分子纳米级组装的探索日益增多的努力，这些小分子组装很大程度上源于纳米科学和技术以外的研究领域的偶然观察。具体来说，我们描述了小分子的纳米级组装体在细胞外和细胞内环境中表现出独特的生物学功能，从而诱导各种细胞反应，例如导致细胞死亡或促进细胞增殖。我们首先调查了纳米级分子组装体的某些共同特征，然后讨论了几个具体的例子，例如细胞中积累的小肽纳米级组装体通过与蛋白质的混杂相互作用选择性地抑制癌细胞，以及糖复合物的纳米级组装体促进增殖干细胞或抑制免疫反应。随后，我们强调纳米尺度组装的时空控制来控制细胞命运，特别阐述了一种范式转换方法——酶指导自组装（EISA），即酶促反应和自组装的整合——用于生成纳米尺度由无害单体组装而成，用于选择性抑制癌细胞。此外，我们引入了一种方便的检测方法，用于研究与细胞环境中小分子纳米级组装体相互作用的蛋白质。此外，我们介绍了使用配体-受体相互作用来催化纳米级组装体的形成。通过说明这些控制小分子纳米级组装体形成并识别其相应蛋白质靶标的实验策略，我们的目的是强调，尽管没有在基因水平上定义，小分子纳米级组装体能够执行许多关键的生物学功能。功能。我们设想小分子的纳米级组装是纳米科学与细胞生物学和生物医学交叉点的新前沿。此外，我们还讨论了小分子纳米级组装体相关潜在生物医学应用的挑战和前景。