While most hydrogels are traditionally formed from polymers, biomolecules can also undergo gelation, as exemplified by proteins (e.g., collagen), enabling numerous applications. Peptide-based low-molecular-weight hydrogels (LMWHs), composed of amino acids, have emerged as innovative materials with broad biomedical and biotechnological potential, attracting commercial interest in the 2010s.^[1] However, natural peptides composed solely of proteinogenic amino acids present several limitations, requiring structural or chemical modifications to enhance their performance.^[2] In parallel, multicomponent approaches, which combine multiple building blocks to form hydrogels, have recently gained prominence as a promising strategy for developing more versatile and efficient systems.^[3]

In this context, we explore emerging hybrid molecules—peptides functionalized with DNA bases (adenine (A), thymine (T), guanine (G), and cytosine (C))—known as nucleopeptides. These compounds have shown encouraging results, yet much remains to be explored to unlock their full potential.^[4] We designed and investigated innovative multicomponent nucleopeptide-based hydrogels, functionalized with one or two DNA nucleobases via peptide nucleic acid (PNA) moieties to enhance stability and supramolecular assembly. Recently, two series were studied, ^PNA[TG]-FEFK/^PNA[AC]-FEFK^[5] and ^PNA[T or C]-FEFE/^PNA[A or G]-FKFK,^[6] the latter exploiting electrostatic complementarity between peptide segments. Using a systematic multi-scale approach, we evaluated the influence of charge and/or nucleobase pair complementarity on gelation kinetics, thermal stability, stiffness, stress resistance, network morphology, and intermolecular interactions. Our results demonstrate that careful component selection enables the fine-tuning of hydrogel properties, yielding highly stiff materials (storage modulus > 1 MPa). Unexpected behaviors were also observed, underscoring the complexity of these hybrid systems and reinforcing their potential for the development of high-performance supramolecular hydrogels.

References: [1] J. Heremans et al., J. Pept. Sci., 2025; [2] A. K. Das, P. K. Gavel, Soft Matter, 2020; [3] D. M. Raymond, B. L. Nilsson, Chem. Soc. Rev., 2018; [4] T. Giraud et al., Nanoscale, 2022; [5] P. Hoschtettler et al., Chem. Sci., 2023; [6] T. Giraud et al., submitted.