A Strong Acid‐Induced DNA Hydrogel Based on pH‐Reconfigurable A‐Motif Duplex

Abstract Under a pH value lower than the pK_a of adenine (3.5), adenine‐rich sequences (A‐strand) form a unique parallel A‐motif duplex due to the protonation of A‐strand. At a pH above 3.5, deprotonation of adenines leads to the dissolution of A‐motif duplex to A‐strand single coil. This pH‐reconfigurable A‐motif duplex has been developed as a novel pH‐responsive DNA hydrogel, termed A‐hydrogel. The hydrogel state is achieved at pH 1.2 by the A‐motif duplex bridging units, which are cross‐linked by both reverse Hoogsteen interaction and electrostatic attraction. Hydrogel‐to‐solution transition is triggered by pH 4.3 due to the deprotonation‐induced separation of A‐motif duplex. The A‐hydrogel system undergoes reversible hydrogel–solution transitions by subjecting the system to cyclic pH shifts between 1.2 and 4.3. An anti‐inflammatory medicine, sulfasalazine (SSZ), which intercalates into A‐motif duplex, is loaded into A‐hydrogel. Its pH‐controlled release from A‐hydrogel is successfully demonstrated. The strong acid‐induced A‐hydrogel may fill the gap that other mild acid‐responsive DNA hydrogels cannot do, such as protection of orally delivered drug in hostile stomach environment against strong acid (pH ~ 1.2) and digestive enzymes.