Fmoc-diphenylalanine (Fmoc-FF) is a low-molecular-weight peptide hydrogelator. This simple all-aromatic peptide can generate self-supporting hydrogel materials, which have been proposed as novel materials for diagnostic and pharmaceutical applications. Our knowledge of the molecular determinants of Fmoc-FF aggregation is used as a guide to design new peptide-based gelators, with features for the development of improved tools. Here, we enlarge the plethora of Fmoc-FF-based hydrogelated matrices by studying the properties of the Fmoc-FFK tripeptide, alone or in combination with Fmoc-FF. For multicomponent matrices, the relative weight ratios between Fmoc-FFK and Fmoc-FF (specifically, 1/1, 1/5, 1/10, and 1/20 w/w) are evaluated. All the systems and their multiscale organization are studied using different experimental techniques, including rheology, circular dichroism, Fourier transform infrared spectroscopy, and scanning electron microscopy (SEM). Preliminary profiles of biocompatibility for the studied systems are also described by testing them in vitro on HaCaT and 3T3-L1 cell lines. Additionally, the lysine (K) residue at the C-terminus of the Fmoc-FF moiety introduces into the supramolecular material chemical functions (amino groups) which may be useful for modification/derivatization with bioactive molecules of interest, including diagnostic probes, chelating agents, active pharmaceutical ingredients, or peptide nucleic acids.

Multicomponent hydrogels (HGs) based on ultrashort aromatic peptides have been exploited as biocompatible matrices for tissue engineering applications, the delivery of therapeutic and diagnostic agents, and the development of biosensors. Due to its capability to gel under physiological conditions of pH and ionic strength, the low molecular-weight Fmoc-FF (N^α-fluorenylmethoxycarbonyl-diphenylalanine) homodimer is one of the most studied hydrogelators. The introduction into the Fmoc-FF hydrogel of additional molecules like protein, organic compounds, or other peptide sequences often allows the generation of novel hydrogels with improved mechanical and functional properties. In this perspective, here we studied a library of novel multicomponent Fmoc-FF based hydrogels doped with different amounts of the tripeptide Fmoc-FFX (in which X= Cys, Ser, or Thr). The insertion of these tripeptides allows to obtain hydrogels functionalized with thiol or alcohol groups that can be used for their chemical post-derivatization with bioactive molecules of interest like diagnostic or biosensing agents. These novel multicomponent hydrogels share a similar peptide organization in their supramolecular matrix. The hydrogels’ biocompatibility, and their propensity to support adhesion, proliferation, and even cell differentiation, assessed in vitro on fibroblast cell lines, allows us to conclude that the hybrid hydrogels are not toxic and can potentially act as a scaffold and support for cell culture growth.

Bone tissue engineering offers a promising alternative to autografts and allografts for treating critical bone defects. Hydrogels, three-dimensional hydrophilic polymer networks, have emerged as leading scaffold materials due to their ability to mimic native extracellular matrix properties while providing tunable biocompatibility, biodegradability, mechanical characteristics, and high water content, enabling nutrient transport and cell viability. These scaffolds can be loaded with bioactive cues, including growth factors, peptides, and nanoparticles, and can deliver stem cells, supporting localised and sustained bone regeneration. Recent advances in hydrogel design have improved osteoinductivity and osteoconductivity through controlled physical, chemical, and mechanical properties, and sophisticated fabrication strategies such as 3D bioprinting and nanostructuring. This review provides a comprehensive overview of hydrogel-based scaffolds for bone tissue engineering, discussing material types, bioactive factor delivery, host tissue interactions, including immune modulation and osteogenic differentiation, and the latest preclinical and clinical applications. Finally, we highlight the remaining challenges and critical design requirements for developing next-generation hydrogels that integrate structural integrity with biological functionality.

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.

This study investigates the use of peptide-based hydrogels as scaffolds for the encapsula-tion and delivery of Peptide Nucleic Acids (PNAs) in drug delivery applications. Ultra-short aromatic peptide-based hydrogels (HGs), such as Fmoc-FF (Nα-fluorenyl methox-ycarbonyl-diphenylalanine), provide an ideal platform for encapsulating biomolecules due to their biocompatibility, self-assembling nature, and ability to form stable, nanostructured networks. The functionalization of these hydrogels with Fmoc-FFX tripep-tides—where X is cysteine (C) or lysine (K)—enhances their ability to interact with PNA sequences. Model four-bases PNA, functionalized with cysteine (C) or glutamic acid (E) residues at the C-terminus, facilitate covalent or electrostatic interactions with the hydro-gel matrix, improving encapsulation efficiency and stabilizing the PNAs. We systemati-cally optimized the composition and ratios of hydrogel components and PNAs to enhance encapsulation efficiency, structural stability, and controlled release profiles. The resulting hydrogels were thoroughly characterized using High-Performance Liquid Chromatog-raphy (HPLC), Electrospray Ionization Mass Spectrometry (ESI-MS), Circular Dichroism (CD), rheology, Fourier-Transform Infrared (FT-IR) spectroscopy, Scanning Electron Mi-croscopy (SEM), Proton Nuclear Magnetic Resonance (¹H-NMR), as well as optical and fluorescence microscopy. Our results demonstrate the potential of these hydrogels as highly effective platforms for stabilizing and delivering PNAs, offering promising pro-spects for the development of innovative nucleic acid-based therapies.