Supramolecular polymer-based biomaterials play a significant role in current biomedical research. In particular, peptide amphiphiles (PAs) represent a promising material platform for biomedical applications given their modular assembly, tunability, and capacity to render materials with structural and molecular precision. However, the possibility to provide dynamic cues within PA-based materials would increase the capacity to modulate their mechanical and physical properties and, consequently, enhance their functionality and broader use. In this study, we report on the synthesis of a cationic PA pair bearing complementary adamantane and β-cyclodextrin host–guest cues and their capacity to be further incorporated into self-assembled nanostructures. We demonstrate the possibility of these recognition motifs to selectively bind, enabling noncovalent cross-linking between PA nanofibers and endowing the resulting supramolecular hydrogels with enhanced mechanical properties, including stiffness and resistance to degradation, while retaining in vitro biocompatibility. The incorporation of the host–guest PA pairs in the resulting hydrogels allowed not only for macroscopic mechanical control from the molecular scale, but also for the possibility to engineer further spatiotemporal dynamic properties, opening opportunities for broader potential applications of PA-based materials.
