Nanofibrous Peptide Hydrogels Leveraging Histidine to Modulate pH-Responsive Supramolecular Assembly and Antibody Release

In this work, we investigate the pH-responsive behavior of multidomain peptide (MDP) hydrogels containing histidine. Small-angle X-ray scattering confirmed that MDP nanofibers sequester nonpolar residues into a hydrophobic core surrounded by a shell of hydrophilic residues. MDPs with histidine on the hydrophilic face formed nanofibers at all pH values tested, but the morphology of the fibers was influenced by the protonation state and the location of histidine in the MDP sequence. MDPs with histidine residues within the hydrophobic face disassemble below physiological pH and form nanofibers at higher pH. Taking advantage of their stimulus-triggered behavior, an anti-PD-1 antibody was loaded into histidine MDP hydrogels to examine pH-dependent differences in payload delivery in vitro. Hydrogels composed of MDPs with histidine on the hydrophilic face demonstrated pH-dependent payload retention. Additionally, they showed significantly slower antibody release and reduced antibody diffusion rates in vitro compared to MDP hydrogels lacking histidine.