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      Capsule-like DNA Hydrogels with Patterns Formed by Lateral Phase Separation of DNA Nanostructures

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          Abstract

          Phase separation is a key phenomenon in artificial cell construction. Recent studies have shown that the liquid–liquid phase separation of designed-DNA nanostructures induces the formation of liquid-like condensates that eventually become hydrogels by lowering the solution temperature. As a compartmental capsule is an essential artificial cell structure, many studies have focused on the lateral phase separation of artificial lipid vesicles. However, controlling phase separation using a molecular design approach remains challenging. Here, we present the lateral liquid–liquid phase separation of DNA nanostructures that leads to the formation of phase-separated capsule-like hydrogels. We designed three types of DNA nanostructures (two orthogonal and a linker nanostructure) that were adsorbed onto an interface of water-in-oil (W/O) droplets via electrostatic interactions. The phase separation of DNA nanostructures led to the formation of hydrogels with bicontinuous, patch, and mix patterns, due to the immiscibility of liquid-like DNA during the self-assembly process. The frequency of appearance of these patterns was altered by designing DNA sequences and altering the mixing ratio of the nanostructures. We constructed a phase diagram for the capsule-like DNA hydrogels by investigating pattern formation under various conditions. The phase-separated DNA hydrogels did not only form on the W/O droplet interface but also on the inner leaflet of lipid vesicles. Notably, the capsule-like hydrogels were extracted into an aqueous solution, maintaining the patterns formed by the lateral phase separation. In addition, the extracted hydrogels were successfully combined with enzymatic reactions, which induced their degradation. Our results provide a method for the design and control of phase-separated hydrogel capsules using sequence-designed DNAs. We envision that by incorporating various DNA nanodevices into DNA hydrogel capsules, the capsules will gain molecular sensing, chemical-information processing, and mechanochemical actuating functions, allowing the construction of functional molecular systems.

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          Most cited references50

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          A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation.

          Many proteins contain disordered regions of low-sequence complexity, which cause aging-associated diseases because they are prone to aggregate. Here, we study FUS, a prion-like protein containing intrinsically disordered domains associated with the neurodegenerative disease ALS. We show that, in cells, FUS forms liquid compartments at sites of DNA damage and in the cytoplasm upon stress. We confirm this by reconstituting liquid FUS compartments in vitro. Using an in vitro "aging" experiment, we demonstrate that liquid droplets of FUS protein convert with time from a liquid to an aggregated state, and this conversion is accelerated by patient-derived mutations. We conclude that the physiological role of FUS requires forming dynamic liquid-like compartments. We propose that liquid-like compartments carry the trade-off between functionality and risk of aggregation and that aberrant phase transitions within liquid-like compartments lie at the heart of ALS and, presumably, other age-related diseases.
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            Coactivator condensation at super-enhancers links phase separation and gene control

            Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here, we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets and MED1-IDR droplets can compartmentalize and concentrate transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in control of key cell identity genes.
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              Routes and mechanisms of extracellular vesicle uptake

              Extracellular vesicles (EVs) are small vesicles released by donor cells that can be taken up by recipient cells. Despite their discovery decades ago, it has only recently become apparent that EVs play an important role in cell-to-cell communication. EVs can carry a range of nucleic acids and proteins which can have a significant impact on the phenotype of the recipient. For this phenotypic effect to occur, EVs need to fuse with target cell membranes, either directly with the plasma membrane or with the endosomal membrane after endocytic uptake. EVs are of therapeutic interest because they are deregulated in diseases such as cancer and they could be harnessed to deliver drugs to target cells. It is therefore important to understand the molecular mechanisms by which EVs are taken up into cells. This comprehensive review summarizes current knowledge of EV uptake mechanisms. Cells appear to take up EVs by a variety of endocytic pathways, including clathrin-dependent endocytosis, and clathrin-independent pathways such as caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft–mediated internalization. Indeed, it seems likely that a heterogeneous population of EVs may gain entry into a cell via more than one route. The uptake mechanism used by a given EV may depend on proteins and glycoproteins found on the surface of both the vesicle and the target cell. Further research is needed to understand the precise rules that underpin EV entry into cells.
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                Author and article information

                Journal
                JACS Au
                JACS Au
                au
                jaaucr
                JACS Au
                American Chemical Society
                2691-3704
                29 November 2021
                24 January 2022
                : 2
                : 1
                : 159-168
                Affiliations
                []Frontier Research Institute for Interdisciplinary Sciences, Tohoku University , Miyagi 980-8579, Japan
                []Department of Computer Science, Tokyo Institute of Technology , Kanagawa 226-8502, Japan
                Author notes
                Author information
                https://orcid.org/0000-0002-3874-2670
                Article
                10.1021/jacsau.1c00450
                8790810
                35098232
                4401d1cb-ed43-456e-bc89-04b281f7f874
                © 2021 The Authors. Published by American Chemical Society

                Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 11 October 2021
                Funding
                Funded by: Asahi Glass Foundation, doi 10.13039/100007684;
                Award ID: NA
                Funded by: Tokyo Tech Advanced Researchers, doi NA;
                Award ID: NA
                Funded by: NICA Fellows program, doi NA;
                Award ID: NA
                Funded by: Japan Society for the Promotion of Science, doi 10.13039/501100001691;
                Award ID: JP20K21828
                Funded by: Japan Society for the Promotion of Science, doi 10.13039/501100001691;
                Award ID: JP20K19918
                Funded by: Japan Society for the Promotion of Science, doi 10.13039/501100001691;
                Award ID: JP20H05970
                Funded by: Japan Society for the Promotion of Science, doi 10.13039/501100001691;
                Award ID: JP20H05935
                Funded by: Japan Society for the Promotion of Science, doi 10.13039/501100001691;
                Award ID: JP20H05701
                Funded by: Japan Society for the Promotion of Science, doi 10.13039/501100001691;
                Award ID: JP20H00619
                Funded by: Japan Society for the Promotion of Science, doi 10.13039/501100001691;
                Award ID: JP19KK0261
                Categories
                Article
                Custom metadata
                au1c00450
                au1c00450

                phase separation,dna nanotechnology,dna hydrogels,water-in-oil droplets,lipid vesicles,microgel capsules,artificial cells,molecular robots

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