Synergistic Multicomponent Nucleopeptide-Based Hydrogels: Harnessing DNA-Base Pairing and Electrostatic Complementarities.

Hydrogels are everyday materials characterized by their remarkable properties, of bridging the gap between liquid and solid states. While most hydrogels are traditionally formed from polymers, biomolecules can also undergo gelation, as seen with proteins (e.g., collagen), enabling numerous applications. Peptide-based low-molecular-weight hydrogels (LMWHs), composed of amino acids, have emerged as innovative materials with a broad range of biomedical and biotechnological applications, gaining commercial interest in the 2010s. However, natural peptides composed solely of proteinogenic amino acids present several drawbacks, requiring structural or chemical modifications to enhance their performance. Additionally, multicomponent approaches, which involve combining multiple compounds to form hydrogels, have recently gained prominence as a promising strategy for developing more versatile and efficient systems. In this context, we explore emerging hybrid molecules, i.e., peptides functionalized with DNA bases (i.e., adenine, thymine, guanine, and cytosine), known as nucleopeptides. These compounds have shown encouraging results, yet much remains to be explored to unlock their full potential. In this study, we present a novel series of six (nucleo)-peptides derived from two distinct peptide sequences, Phe-Glu-Phe-Glu and Phe-Lys-Phe-Lys, negatively and positively charged at physiological pH, respectively, making them complementary in terms of electrostatic interactions. These peptides are functionalized with one of the four DNA nucleobases, introduced via a peptide nucleic acid (PNA) moiety. Thus, through a comprehensive multiscale systematic study, we report herein on the impact of charge complementarity and/or nucleobase-pair complementarity on the mechanical and physicochemical properties of the resulting multicomponent hydrogels (including gelation time, sol-gel transition temperature, stiffness, resistance to external stress, fibrillar network morphology, etc.). Then, the results highlight the undeniable potential of this approach, demonstrating that careful selection of components allows the fine-tuning of hydrogel properties. Interestingly, our findings reveal unexpected behaviors, underscoring the complexity of these bioinspired hybrid multicomponent systems while reinforcing their potential for the development of high-performance and innovative supramolecular hydrogels.