Hierarchical Structures in Macromolecule‐Assembled Synthetic Cells

Abstract

Various models of synthetic cells have been developed as researchers have sought to explore the origins of life. Based on the fact that structural complexity is the foundation of higher‐order functions, this review focuses on hierarchical structures in synthetic cell models that are inspired by living systems, in which macromolecules are the dominant participants. The underlying advantages and functions provided by biomimetic higher‐order structures are discussed from four perspectives, including hierarchical structures in membranes, in the composite construction of membrane‐coated artificial cytoplasm, in organelle‐like subcellular compartments, as well as in synthetic cell–cell assembled synthetic tissues. In parallel, various feasible driving forces and approaches for the fabrication of such higher‐order structures are showcased. Furthermore, both the implemented and potential applications of biomimetic systems, bottom‐up biosynthesis, biomedical tissue engineering, and disease therapy are highlighted. This thriving field is gradually narrowing the gap between fundamental research and applied science.

Hierarchical Structuration in Protocellular System

“…[59][60][61][62][63][64][65][66] Due to the dynamic modulation of the internal micro-environment, the internal compartments could be generated through liquid-liquid phase separation (LLPS), [49,50] which could be used to simulate the dynamic formation of membranelles organelles in living cells (Figure 3a). To date, different approaches, including diffusion of signaling molecule, [27,51,67] alteration of pH, [58,68] temperature or osmotic pressure, [34,36,[69][70][71][72][73][74] and light irradiation, [75][76][77][78][79] have been developed to regulate the dynamic LLPS process within a protocell.…”

“…[69] The dynamic intracellular coacervate formation could also be regulated by altering environmental pH. [58,68] Last et al demonstrated that a step increase in pH in the external environment from 4 to 9 induced the deprotonation of the ATP molecule, which was pre-encapsulated in the lipid vesicle. The negatively charged ATP could form coacervate microdroplets with positively charged pLL within the protocell (Figure 3b).…”

Utilizing bioprinting to engineer spatially organized tissues from the bottom-up

“…Several reviews have already summarized fabrication and assembly techniques of modular tissue engineering [ 5 , 8 – 11 ]. In this review, we focus on applications of bioprinting in bottom-up tissue engineering, especially its capability of mimicking physiological complexity to form spatially organized tissues.…”

Sculpting DNA-based synthetic cells through phase separation and phase-targeted activity

“…1,5 Particularly challenging in the context of synthetic cell engineering is the production of sufficiently complex and robust cell-like architectures containing multiple compartments that serve to localise, segregate, and regulate function and environment. 6,7 These enclosures are often membranebased, constructed from phospholipids and/or fatty acid vesicles, [8][9][10][11][12] polymersomes, 13,14 or proteinosomes, 15,16 but alternative membraneless architectures are emerging in the form of hydrogel capsules, coacervates, or synthetic condensates. [17][18][19][20][21] Microfluidics is a typical strategy for producing synthetic cell scaffolds, being particularly effective at generating monodisperse and nested structures in small quantities.…”