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

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.