Mechanically Enhanced Ultrashort Peptide Hydrogels for pH-Triggered Release

Ultrashort peptide-based hydrogels represent an attractive class of supramolecular soft materials due to their minimalistic design, chemical versatility, and potential for translational applications. Classical Fmoc-dipeptides, particularly Fmoc-FF, are well established as efficient low-molecular-weight hydrogelators; however, controlling their aqueous solubility and gelation behavior across physiologically relevant conditions remains a key design challenge for injectable and in situ forming materials. Here, we report a pH-responsive injectable hydrogel based on a dipeptide incorporating the unnatural amino acid Fmoc-β-(3-pyridyl)-l-alanine (Fmoc-3-Pal-OH). Introduction of the pyridyl moiety provides a well-defined protonation-deprotonation equilibrium that acts as a molecular switch to regulate the supramolecular self-assembly. Deprotonation in the pH range 6.0-8.0 promotes spontaneous hydrogel formation under mild conditions, while protonation at acidic pH induces a controlled network disassembly. The hydrogel system was comprehensively characterized as a function of the concentration and buffer conditions using fluorescence spectroscopy, circular dichroism, Fourier-transform infrared spectroscopy, scanning electron microscopy, and rheology. pH modulation enables fine control over nanofibrillar organization and viscoelastic properties, yielding mechanically stable hydrogels with tunable stiffness values comparable to those of soft biological tissues. The pH-dependent assembly behavior was further exploited to regulate drug release. Encapsulation of curcumin as a hydrophobic model compound demonstrated high loading capacity and sustained release under neutral conditions, while acidic pH triggered an accelerated release through protonation-induced network collapse. Overall, the results achieved by this research open the way to a simple and robust molecular design strategy to overcome key limitations of conventional Fmoc-based hydrogelators and highlight the potential of protonation-controlled ultrashort peptide assemblies as adaptable polymer-like networks for stimuli-responsive soft materials and drug delivery applications.