Reconfigurable A-motif, i-motif and triplex nucleic acids for smart pH-responsive DNA hydrogels

Integrating dynamic reconfigurable DNA crosslinking units, smart DNA hydrogels have demonstrated sol–gel transition, shape memory, self-healing, sensing, cargo encapsulation and delivery. They are engineered to be responsive to external stimuli, such as light, pH, ions, fuel strands, thermal trigger, chemical and biocatalytic reactions for applications in material science, chemistry and biomedicine. This review examines the recent advances of pH-sensitive nucleic acid structures, especially A-motif, i-motif and triplex, for pH-responsive DNA hydrogels. Structural details of pH-triggered, switchable A-motif, i-motif and triplex configurations are presented as the basis for the construction of pH-responsive DNA hydrogels. The physicochemical properties of pH-responsive DNA hydrogels subjecting to ambient pH changes, as well as their applications in shape modulation, self-healing, drug release, sensing, therapy, soft matter, etc. are summarized. In addition, the engineering of pH-responsive DNA hydrogels or nanogels in mildly acidic tumor microenvironment (TME) or compartments of cells (e.g., endosomes or lysosomes), as well as the processing of biological information and output of intelligent signals, are highlighted. The latest research directions and future challenges are discussed, including novel pH-induced secondary DNA structures, pH-dictated mechanical actuators mimicking living matter, and “live” hydrogels as “artificial cells” with autonomous functions.