Self‐Assembly Pathway Influence on Dehydropeptide‐Based Gel Properties and Drug Release

Low-molecular-weight peptide-based hydrogels formed through self-assembly have emerged as promising candidates for biomedical applications. While the self-assembly process is known to affect the network morphology, its impact on mechanical properties and drug delivery remains poorly understood. In this work, it is explored how different gelation conditions influence the morphology, properties, and drug release profiles of dehydropeptide-based gels. Additionally, it is presented and analyzed, for the first time, the crystal structure of a naphthalene N-capped dehydropeptide (2-Naph-L-Phe-Z-ΔPhe-OH), which reveals a maximum pore diameter of ≈4.08 Å. By changing the preparation conditions, it is found that the stiffness of the hydrogels can vary by nearly three orders of magnitude. Employing spectroscopic and imaging techniques, the relationship between the gelation methods and the resulting mechanical properties is investigated. These findings suggest that the assembly structure, morphology, and non-covalent interactions significantly influence the release profile of model drugs such as doxorubicin, methotrexate, and curcumin. These results provide valuable insights into how preparation conditions can impact the properties of peptide-based hydrogels and their drug release profiles.