Coupling materials chemistry systems to biological processes is a promising way to rationally modulate lysosomal functions. A proton‐driven dynamic assembly of a DNA nanoframework inside cells coupled with the lysosome‐mediated endocytosis pathways/lysosomal maturation, gives the rational modulation of lysosomal functions, which we term “lysosome interference”. Through lysosome‐mediated endocytosis, the DNA nanoframework with acid‐responsive semi‐i‐motif enters the lysosome and assembles into an aggregate in a process triggered by lysosomal acidity. The aggregate is suitable for long‐term retention. The consumption of protons resulted in lysosomal acidity reduction and hydrolase activity attenuation, thus hindering the degradation of nucleic acid drugs in the lysosome and improving gene silencing effects. This study shows a new way to achieve lysosome interference by coupling the subcellular microenvironment with a precisely programmable assembly system.
models have attracted considerable attentions in order to unravel the inherent complexity. Although engineering modern cells has achieved some progress, [2] the arbitrary elimination of genomic information could probably remove some distinguished characteristics (top-down strategy). Building chemical systems that resemble the structure and behaviors of living cells by stepwise integration of pivotal components is also conceivable (bottom-up strategy). [3] These synthetic systems with biomimetic cellularity provide conceptual pathway from inanimate matter to artificial life, which are often known as artificial cells. [4] Due to the lack of full comprehension about the molecular mechanism of living cells, laborious reconstitution of complicated networks would be difficult and the disparities of protein behaviors in the artificial cells have been observed. Herein, we prefer to construct artificial cells by preserving certain endogenous machinery already existing in living cells. Such principle is conducible for maintaining essential features of living cells while leaving design space for synthetic biologists to study specific cellular behavior in bottom-up manner. [5] Cell-free system, also referred to as in vitro transcription and translation system is a universal toolbox to study the organisms of cell biology. [6] Cell-free extracts inherit most of the endogenous machinery including functional macromolecules as well as metabolic networks and the addition of desired resources could initiate coupled protein expressions. Indeed, the first appearance of cell-free systems could date back to 1961 when Nirenberg and Matthaei deciphered the genetic codes. [7] Featured by the accessible utilization of molecular machinery, cellfree systems could circumvent the frangibility and membrane barrier of biological cells. The transformative development of protein synthesis using recombinant elements (PURE) system with well-defined components greatly enhances the systemic manipulation and controllability. [8] In principle, the quintessence behind cell-free system is the central dogma that reflects the flow of genetic information, from plasmid DNA to messenger RNA (mRNA), to eventually make functional proteins. As such, artificial cells encapsulated with cell-free system could serve as the valuable candidate to construct numerous biological processes. [9] The powerful ability of protein expressions, which is deprived in other synthetic systems, offers advantageous scenario for enzymatic processes that are also guided by flexible and programmable regulations of gene circuit. [10] The execution of larger genetic programs could further permit the construction of complex biochemical systems. [11] More importantly, Artificial cells that mimic the architectural and functional characteristics of living cells not only shed light on the physical principle of life but also facilitate development in the areas such as cell engineering and biomedicine. Cell-free systems carry out the central dogma that refers to the transcription and translation ...
Precise assembly of biomolecules into functional aggregate structures represents a key characteristic of nature living cells, and is critical for the cellular processes. The construction of artificial aggregates in living cells by responding to intracellular specific stimuli has been applied in elucidating molecular mechanisms of naturally cellular processes and interfering with cellular processes, which is potential and significant in biomedicine. DNA (deoxyribonucleic acid) features sequence programmability, precise assembly and versatility, and therefore is regarded as the potential candidate for constructing versatile functional aggregates in living cells. In this review, we summarize our recent efforts of employing DNA to in situ construct versatile aggregates in living cells via responding intracellular triggers, and the subsequent bio‐interference of the DNA aggregates. Finally, we discuss the remaining challenges and opportunities in the field, and envision that rational design and construction of versatile DNA aggregates in living system would be a promising solution for precision and personalized therapeutics.
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