Endoscopically Deliverable Polymer Adhesives with pH-Triggered Multiple Molecular Evolution for Gastric Ulcer Repair

Hydrogel adhesives show promise for gastric ulcer treatment, while facing challenges in endoscopic delivery, wet adhesion, and long-term gastric retention. Here, we engineered a sequential pH-responsive adhesive (PNMH) by polymerizing β-carboxylic-amide-functionalized N-acryloyl phenylalanine and hydroxyethyl acrylamide. Acid-induced protonation followed by hydrolysis of the β-carboxylic amide drives a pH-triggered quadruple evolution of intermolecular interactions from electrostatic repulsion to hydrophobicity-assisted hydrogen bonding, then to hydrophobicity-assisted electrostatic interaction, and finally to cation–π interaction. This unique mechanism enables facile endoscopic administration of PNMH and ultrafast gelation within ∼4 s upon exposure to gastric acid, forming a robust network and simultaneously displacing interfacial water to achieve immediate tissue adhesion (∼24.1 kPa). Furthermore, the interfacial adhesion strength with wet gastric tissue progressively intensifies to 34.3 kPa in the early stage of hydrolysis while maintaining long-term interfacial integration over 30 days under simulated gastric conditions. Moreover, PNMH exhibits a prolonged in vivo residence time of more than 4 days through in situ injection into the rat stomach. Rat and pig experiments demonstrate that PNMH, as a durable shield, protects ulcers from gastric acid/pepsin erosion and orchestrates healing through attenuating immune activation, suppressing matrix metalloproteinase-9 overexpression and promoting cytoskeleton-driven restoration of the mucosal barrier. Our work presents an advanced molecular design strategy for gastric-resistant polymer adhesives and provides a promising candidate for clinical gastric ulcer treatment.