Phenylboronic acid (PBA)-containing hydrogels (HGs),
capable of
glucose-responsive insulin release, have shown promise in diabetes
management in preclinical studies. However, sustainable material usage
and attaining an optimum insulin release profile pose a significant
challenge in such HG design. Herein, we present the development of
a straightforward fabrication strategy for glucose-responsive protein-polymer
hybrid HGs (PPHGs). We prepare PPHGs by crosslinking polyvinyl alcohol
(PVA) with various nature-abundant proteins, such as bovine serum
albumin (BSA), egg albumin, casein, whey protein, and so forth, using
formylphenylboronic acid (FPBA)-based crosslinkers. We showcase PPHGs
with diverse bulk rheological properties that are appropriately modulated
by the positions of aldehyde, boronic acid, and fluorine substitutions
in the FPBA-crosslinker. The orthogonal imine and boronate ester bonds
formed by FPBAs are susceptible to the acidic pH environment and glucose
concentrations, leading to the glucose-responsive dissolution of the
PPHGs. We further demonstrate that by an appropriate selection of
FPBAs, glucose-responsive insulin release profiles of the PPHGs can
be precisely engineered at the molecular level. Importantly, PPHGs
are injectable, incur no cytotoxicity, and, therefore, hold great
potential as smart insulin for in vivo applications in the near future.