Engineering Hibiscus‐Like Riboflavin/ZIF‐8 Microsphere Composites to Enhance Transepithelial Corneal Cross‐Linking

Abstract Riboflavin‐5‐phosphate (RF) is the most commonly used photosensitizer in corneal cross‐linking (CXL), but its hydrophilicity and negative charge limit its penetration through the corneal epithelium into the stroma. To enhance the corneal permeability of RF and promote its efficacy in the treatment of keratoconus, novel hibiscus‐like RF@ZIF‐8 microsphere composites [6RF@ZIF‐8 NF (nanoflake)] are prepared using ZIF‐8 nanomaterials as carriers, which are characterized by their hydrophobicity, positive potential, biocompatibility, high loading capacities, and large surface areas. Both hematoxylin and eosin endothelial staining and TUNEL assays demonstrate excellent biocompatibility of 6RF@ZIF‐8 NF. In in vivo studies, the 6RF@ZIF‐8 NF displayed excellent corneal permeation, and outstanding transepithelial CXL (TE‐CXL) efficacy, slightly better than the conventional CXL protocol. Furthermore, the special hibiscus‐like structures of 6RF@ZIF‐8 NF meant that it has better TE‐CXL efficacy than that of 6RF@ZIF‐8 NP (nanoparticles) due to the larger contact area with the epithelium and the shorter RF release passage. These results suggest that the 6RF@ZIF‐8 NF are promising for transepithelial corneal cross‐linking, avoiding the need for epithelial debridement.