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 (pKa 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 (pKa 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 (pKa 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.

Programming the Assembly of Oligo-Adenine with Coralyne into a pH-Responsive DNA Hydrogel

“…In the construction of pH-responsive DNA hydrogels, dynamic reconfigurable DNA structures governed by pH variations, such as A-motif, − i-motif, , C + ·G-C and T·A-T triplex, ,, adenine-cyanuric acid (A-CA) triplex, are harnessed as the pivotal cross-linking elements. To facilitate comparisons, the pH responsiveness and conformational transitions of these DNA structures are briefly summarized in Figure .…”

“…By employing pure DNAs or DNA copolymers as the three-dimensional cross-linking networks, DNA hydrogels have attracted much research interest recently due to their high sequence designability, programmability, structural predictability, and biocompatibility. Besides conventional assembly of DNA strands through Watson–Crick base-pairing, noncanonical DNA configurations, including A-motif, − i-motif, , triplex, , G-quadruplex, trans / cis -azobenzene units, metal ion-bridged structures, and DNAzyme, are developed into smart stimuli-responsive DNA hydrogels that can be dynamically programmed by external triggers/counter-triggers, such as pH, ions, small molecule, light, temperature, and chemical/biocatalytic interactions. , Diverse applications, including extracellular matrix, , cell capture and release, shape memory/modulation, , biosensing, , bioprinting, patterning, , anticounterfeiting, load encapsulation and release, − environmental applications, and soft robotics, have been demonstrated recently. Of notable significance is the controlled loading and release of therapeutics from stimuli-responsive DNA hydrogels, particularly in the context of therapies such as cancer treatment .…”

Oligo-Adenine and Cyanuric Acid Supramolecular DNA-Based Hydrogels Exhibiting Acid-Resistance and Physiological pH-Responsiveness

“…Endogenous H + /OH – is also more advantageous in DNA hydrogel manipulation and signal transduction than exogenous triggers (e.g., light) . Upon construction of pH-responsive DNA hydrogels, i-motif is the most frequently used functional unit, − followed by triplexes − and the recent A-motif configuration, ,, in which i-motif is formed under mild acid (pH 5.0), C + ·G-C and T·A-T triplexes are generated at mildly acidic pH and neutral pH, respectively, and the parallel A-motif is assembled under highly acidic environment (pH 1.0–3.0). However, limited pH-responsive DNA configurations impede the development of novel pH-triggered DNA hydrogels, which could potentially be solved by novel pH-induced structures beyond the A-T-G-C alphabet, such as low-molecular-weight cofactor reprogrammable DNA conjugates. , …”