Nanoscale assemblies of small molecules control the fate of cells

Abstract

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.

The enzyme-instructed assembly of the core of yeast prion Sup35 to form supramolecular hydrogels

“…This result implies the simple enhancement of the self-assembly ability may lead to unexpected results. This work, thus, provides a new insight for understanding of cytotoxicity or cell compatibility of nanoscale assemblies of small molecules, a subject 50 receives less attention but warrants further exploration.…”

Self-assembled peptide nanomaterials for biomedical applications: promises and pitfalls

“…1,7 Just like higher hierarchical biomolecules in nature (such as proteins, DNA, and polysaccharides), most self-assembled molecules are formed by the interaction of individual monomers through weak, noncovalent interactions, including electrostatic interactions, hydrophobic interactions, hydrogen bonds, van der Waals interactions, and π-π stacking forces. 3,8 Even though individual noncovalent forces are very weak (eg, hydrophobic forces ,10 kcal/mol, electrostatic forces =1-20 kcal/mol, hydrogen bonds =2-30 kcal/mol, and π-π aromatic stacking =0-10 kcal/mol), the combination of several noncovalent forces together can generate very stable and well-organized structures. 8 There are several advantages of developing self-assembled materials through noncovalent bonds compared to covalent forces.…”

“…3,8 Even though individual noncovalent forces are very weak (eg, hydrophobic forces ,10 kcal/mol, electrostatic forces =1-20 kcal/mol, hydrogen bonds =2-30 kcal/mol, and π-π aromatic stacking =0-10 kcal/mol), the combination of several noncovalent forces together can generate very stable and well-organized structures. 8 There are several advantages of developing self-assembled materials through noncovalent bonds compared to covalent forces. For example, To maximize the formation of as many noncovalent forces as possible, the major component of self-assembled molecules has an amphiphilic structure with both hydrophobic and hydrophilic portions.…”

“…Owing to such unique properties in self-assembled peptides, they have been used for numerous applications, including storing bioinformation via their various sequences, peptide folding, fast and easy synthesis, a variety of functionalization methods, and their programmed responses to external stimulations (such as pH value, ion concentration, and hydrophobicity). 8,11 In terms of the higher hierarchical structure of selfassembled peptides, their stability depends on the monomer structure in terms of the length of the amino acid chain and the shape of the functional group. 12 At the same time, the external environment, including temperature, pH, ionic strength, and mechanical force, can affect or reverse the self-assembly process.…”

Heterotypic supramolecular hydrogels

“…Being referred as hydrogelators, the small molecules self-assemble in water to form the viscoelastic 3-D network to hold water, which results in a colloidal soft material. Drive by non-covalent interactions (e.g., hydrogen bonding, Van der Waals interactions, and charge interactions) in water, supramolecular hydrogels share some common properties with extracellular matrix (ECM) 1 of cells, and are emerging as a new type of versatile biomaterials to be applied in many areas, such as tissue engineering 2, 3 , drug delivery 4, 5 , wound healing 6 , catalysis 7, 8 , and control of cell fate 9–12 .…”