Modular Design and Bonding Mechanism of Internal Boron–Nitrogen Coordinated Boronic Ester Hydrogels with Alkaline pH Responsiveness and Tunable Gelation pH

Boronic ester hydrogels have been widely used in biomedical fields for their stimuli responsiveness to multiple disease-related triggers. However, the restricted pH for gelation and the poor hydrolysis stability limit their application in variable physiological microenvironments. Here, we report a modular conjugation method for designing internal boron–nitrogen coordinated boronic ester (IBNCB) hydrogels by constructing polymers with phenylboronic acid or N,N-bis(2-hydroxyethyl) moieties based on amides. Eight distinct IBNCB hydrogel models composed of polymer/polymer or polymer/micromolecule were prepared, exhibiting a unique pH responsiveness in the alkaline environment, an enhanced hydrolysis stability, bidirectional pH-tunable mechanical properties, and a lowered and tunable pH for gelation. In addition, the IBNCB hydrogels maintained a sol–gel transitional responsiveness to reactive oxygen species (ROS), glucose, and temperature. Especially, we found that the pH required to form an ideal IBNCB hydrogel should be greater than the pKa of phenylboronic acid but lower than the pKa of N,N-bis(2-hydroxyethyl), and reducing the pKa of phenylboronic acid could lower the gelation pH. The pKa of the tertiary amine in N,N-bis(2-hydroxyethyl) was shown to be important in the creation of the B–N coordination bond, which influenced the formation of the IBNCB bond. Finally, we explored the effect of the main chain’s charge on gelability and proposed the dynamic equilibrium mechanism of IBNCB bonds in the hydrogel. We expect that the multi-stimuli-responsive IBNCB hydrogels will provide a new strategy for designing smart materials sensitive to physicochemical signals. Furthermore, the amide-based modular conjugation could be exploited to generate a theoretically limitless number of novel IBNCB materials including microgels, polymer vesicles, and micro–nano particles.