A pH‐Cascaded DNA Hydrogel Mediated by Reconfigurable A‐motif Duplex, i‐Motif Quadruplex, and T·A‐T Triplex Structures

Abstract Governed by pH‐configurable A‐motif, i‐motif and T·A‐T triplex configurations, a cascaded DNA hydrogel subjecting to diverse pH values is presented. Under highly acidic conditions (pH 1.1), N1 protonation of adenine (p K a 3.5) in A‐strands generates AH + ‐H + A units, resulting in a parallel A‐motif duplex crosslinked hydrogel. Under mild acid conditions (pH 5.2), the dissociation of A‐motif duplex into single A‐strands occurs due to the deprotonation of adenine, while N3 protonation of cytosine (p K a 6.5) in C‐strands creates hemi‐protonated C:C + units, resulting in i‐motif bridged hydrogel. At neutral pH (pH 7.2), deprotonation of cytosine separates i‐motif crosslinkers. Simultaneously, the addition of auxiliary T‐strands results in the N3 protonation of thymine (p K a 10), generating T·A‐T triplex stabilized hydrogel. Under mildly alkaline conditions (pH 10.2), T·A‐T triplex separates into single T‐stands and A‐T duplex, resulting in the disassembly of DNA hydrogel. Therefore, a stepwise pH‐cascaded DNA hydrogel dictates the formation of structures following the pH steps 1.1 → 5.2 → 7.2 → 10.2 where pH‐triggered DNA secondary structures, including A‐motif, i‐motif and T·A‐T triplex, stabilize the hydrogel. The study advances DNA hydrogels from single pH‐responsiveness to multiple cascaded pH values, which opens up new possibilities for the development of smart hydrogels capable of adapting to various environmental conditions.