Investigating the Interactions of Peptide Nucleic Acids with Multicomponent Peptide Hydrogels for the Advancement of Healthcare Technologies

This study reports the development of peptide-based hydrogels for the encapsulation and controlled release of peptide nucleic acids in drug delivery applications. Ultrashort aromatic peptides, such as Fmoc-FF, self-assemble into biocompatible hydrogels with nanostructured architectures. The functionalization of tripeptides (Fmoc-FFK and Fmoc-FFC) with lysine (K) or cysteine (C) enables electrostatic or covalent interactions with model PNAs engineered with glutamic acid or cysteine residues, respectively. Hydrogels were polymerized in situ in the presence of PNAs, and component ratios were systematically varied to optimize mechanical properties, loading efficiency, and release kinetics. The formulations obtained with a 1/10 ratio of Fmoc-FF(K or C)/Fmoc-FF provided an optimal balance between structural integrity and delivery performance. All hydrogel formulations demonstrated high stiffness (G' > 19,000 Pa), excellent water retention, and minimal swelling under physiological conditions (ΔW < 4%). The release studies over 10 days showed that electrostatic loading enabled faster and higher release (up to 90%), while covalent bonding resulted in slower, sustained delivery (~15%). These findings highlight the tunability of the hydrogel system for diverse therapeutic applications.