Extracellular matrix (ECM) provides essential supports three dimensionally to the cells in living organs, including mechanical support and signal, nutrition, oxygen, and waste transportation. Thus, using hydrogels to mimic its function has attracted much attention in recent years, especially in tissue engineering, cell biology, and drug screening. However, a hydrogel system that can merit all parameters of the natural ECM is still a challenge. In the past decade, deoxyribonucleic acid (DNA) has arisen as an outstanding building material for the hydrogels, as it has unique properties compared to most synthetic or natural polymers, such as sequence designability, precise recognition, structural rigidity, and minimal toxicity. By simple attachment to polymers as a side chain, DNA has been widely used as cross-links in hydrogel preparation. The formed secondary structures could confer on the hydrogel designable responsiveness, such as response to temperature, pH, metal ions, proteins, DNA, RNA, and small signal molecules like ATP. Moreover, single or multiple DNA restriction enzyme sites could be incorporated into the hydrogels by sequence design and greatly expand the latitude of their responses. Compared with most supramolecular hydrogels, these DNA cross-linked hydrogels could be relatively strong and easily adjustable via sequence variation, but it is noteworthy that these hydrogels still have excellent thixotropic properties and could be easily injected through a needle. In addition, the quick formation of duplex has also enabled the multilayer three-dimensional injection printing of living cells with the hydrogel as matrix. When the matrix is built purely by DNA assembly structures, the hydrogel inherits all the previously described characteristics; however, the long persistence length of DNA structures excluded the small size meshes of the network and made the hydrogel permeable to nutrition for cell proliferation. This unique property greatly expands the cell viability in the three-dimensional matrix to several weeks and also provides an easy way to prepare interpenetrating double network materials. In this Account, we outline the stream of hydrogels based on DNA self-assembly and discuss the mechanism that brings outstanding properties to the materials. Unlike most reported hydrogel systems, the all-in-one character of the DNA hydrogel avoids the "cask effect" in the properties. We believe the hydrogel will greatly benefit cell behavior studies especially in the following aspects: (1) stem cell differentiation can be studied with solely tunable mechanical strength of the matrix; (2) the dynamic nature of the network can allow cell migration through the hydrogel, which will help to build a more realistic model to observe the migration of cancer cells in vivo; (3) combination with rapidly developing three-dimension printing technology, the hydrogel will boost the construction of three-dimensional tissues and artificial organs.

A supramolecular double network hydrogel is presented by physical interpenetration of DNA and cucurbit[8]uril networks. In addition to exhibiting an increase in strength and thermal stability, the double network hydrogel possesses excellent properties such as stretchability, ductility, shear-thinning, and thixotropy. Moreover, it is enzymatically responsive to both nuclease and cellulase, as well as small molecules, showing great potential as a new soft material scaffold.

DNA hydrogel has aroused widespread attention because of its unique properties. In this work, the DNA-modified magnetic nanoparticles were integrated into the mainframe of DNA hydrogel, resulting in DNA-MNP hydrogel. Under the magnetic field, this hydrogel can be remotely deformed into various shapes, driven to jump between two planes and even climb the hill. By applying various triggers, such as temperature, enzyme, and magnetic field, DNA-MNP hydrogel can specifically undergo sol-gel transition. This work not only imparts DNA hydrogel with a new fold of property but also opens a unique platform of such smart materials for its further applications.

DNA hydrogels have been demonstrated with important applications in three-dimensional cell culture in vitro due to their good biocompatibility, biodegradability, and permeability. In these applications, to observe the cell morphology and functions in situ, immobilization, labeling, and imaging processes are involved, which requires good stability of the hydrogels during washing and immersion. To improve the stability of the hydrogels for better imaging, here we built a covalent second network in a DNA supramolecular hydrogel by in situ polymerization and successfully constructed a stable three-dimensional transparent system for cell culture and observation. This strategy has been proved to be efficient in enhancing the mechanical properties and immobilizing the cells inside the hydrogel, which can be applied for immunostaining and cell imaging.

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