l-Histidine (l-His) molecules can form highly ordered fluorescent crystals with tunable size and geometry. The polymorph A crystal of l-His contains hydrophobic domains within the structure's interior. Here, we demonstrate that these hydrophobic domains can serve as vehicles for highly efficient entrapment and transport of hydrophobic small molecules. This strategy shows the ability of l-His crystals to mask the hydrophobicity of various small molecules, helping to address issues related to their poor solubility and low bioavailability. Furthermore, we demonstrate that we can modify the surface of these crystals to define their function, suggesting the significance of l-His crystals in designing site-specific and bioresponsive platforms. As a demonstration, we use l-His crystals with loaded doxorubicin, featuring hyaluronic acid covalently bonded on the crystal surface, controlling its release in response to hyaluronidase. This strategy for entrapment of hydrophobic small molecules suggests the potential of l-His crystals for targeted drug-delivery applications.
Keywords: drug delivery; hydrophobic small molecules; l-histidine; natural fluorescent crystals.