Bioresponsive DNA Hydrogels: Beyond the Conventional Stimuli Responsiveness.

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Bioresponsive hydrogels can respond to various biological stimuli by a macroscopic change of physical state or by converting biochemical inputs into biological or mechanical outputs. These materials are playing an increasingly important role in a wide variety of applications, especially in the biological and biomedical fields. However, the design and engineering of intriguing bioresponsive materials with adequate biocompatibility and biodegradability have proven to be a great challenge. DNA, on the other hand, possesses many unique and fascinating properties, including its indispensable genetic function, broad biocompatibility, precise molecular recognition capability, tunable multifunctionality, and convenient programmability. Therefore, DNA has provided crucial prerequisites for the exploration of novel bioresponsive hydrogels and has since become an ideal building block for the construction of novel materials. In this Account, we describe our efforts over more than a decade to develop DNA-based materials including bioresponsive hydrogels. These DNA hydrogels were created through either chemical cross-linking or physical entanglement among DNA chains. We further divided them into two categories: pure DNA-based and hybrid DNA-based hydrogels. For the pure DNA-based hydrogels, we developed the first bulk DNA hydrogel entirely from branched DNA by using enzymatic ligation. Certain drugs were encapsulated in such hydrogels in situ and released in a controllable manner under the stimulation of environmental factors such as nucleases and/or changes in ionic strength. Furthermore, we prepared a protein-producing hydrogel (termed a "P-gel") by ligating X-shaped DNA (X-DNA) and linear plasmids. Following the central dogma of molecular biology, this hydrogel responded to enzymes and substrate and converted them into proteins. This was the first example showing that a hydrogel could be employed to produce proteins without the involvement of live cells. This might also be the first attempt to create cell-like hydrogels that will be ultimately bioresponsive. In addition, we also constructed a DNA physical hydrogel via entanglement of DNA chains elongated by a special polymerase: Phi29. This hydrogel (termed a "meta-hydrogel") exhibited a "meta" property: freely reversible change between liquidlike and solidlike states through stimulation by water molecules. Besides these pure DNA-based hydrogels, we also created a hybrid DNA-based hydrogel: a DNA-clay hybrid hydrogel utilizing electrostatic interactions between DNA and clay nanocrystals. We discovered a synergistic responsiveness in biochemical reaction in this hydrogel, suggesting that a DNA-clay hydrogel might be the environment for the origination of life and that DNA and clay might have been coevolving during early evolution. In summary, DNA links the nonbiological world with biological processes by virtue of its bioresponsiveness. We envision that bioresponsive DNA hydrogels will play an irreplaceable part in the development of future evolvable materials such as soft robots and artificial cells.