Cascade DNA Structural Transitions Enable Stimuli-Responsive Hydrogels

Cascade interactions are fundamental to enzyme catalysis and cellular activities, enabling dynamic and adaptive responses to environmental stimuli. DNA-based cascade systems have been widely employed to mimic biological processes, such as immune responses and DNAzyme catalysis, achieved mainly through the hybridization interaction. Herein, we present a cascade DNA system involving single-stranded sequences, noncanonical cofactor-bridged duplexes, and canonical duplexes to construct and dissociate hydrogel matrices. In this work, thymine-rich oligonucleotides (T-strands) exist as single-stranded random coils in a buffer at pH 7.2. Upon the introduction of a low-molecular-weight cofactor, melamine (MA), a supramolecular noncanonical configuration, termed the T-MA-T duplex, is formed. Subsequent addition of adenine-rich oligonucleotides (A-strands) to the system leads to the replacement of MA cofactors and the formation of more energetically favorable canonical A-T duplex structures. These consecutive structural transitions are further utilized as dynamic bridging elements in stimuli-responsive DNA hydrogels, facilitating liquid–hydrogel–liquid phase transitions. Moreover, we demonstrate precisely controlled release profiles of doxorubicin from the DNA hydrogel. This approach, leveraging both noncanonical and canonical DNA configurations in triggered cascade structural transitions, opens avenues for developing molecular switches, electronic nanodevices, adaptive materials, and other advanced applications.