Zwitterionic Dipeptide Surface Functionalization of Detonation Nanodiamond for Enhanced Control in Biological Environments

Utilizing nanoparticles as innovative theranostic agents for biomedical applications requires full control over the material's properties to dictate their interactions within a biological environment. Owing to its versatile surface chemistry and high biocompatibility, nanodiamond (ND) represents a promising platform for novel healthcare treatments. To ensure the performance and safety of NDs, their properties and behavior must remain unchanged upon administration, a key challenge in nanomedicine. Recently, zwitterionic surface modifications have emerged as new strategies to substantially improve protein-repelling properties and biocompatibility of nanomaterials. Using for the first time covalently conjugated zwitterionic dipeptides as surface modulators for ND particles, we were able to provide a readily accessible, reproducible, and tunable functionalization. The obtained particles demonstrate enhanced colloidal stability and conservation of particle size over a broad pH range and in different protein-containing media compared to the starting material. By simple selection of different dipeptides, we can carefully tailor the biocompatibility and cellular uptake of functionalized NDs. We reveal the functionalized NDs' behavior in biologically relevant 3D organotypic models and how different dipeptide-functionalized NDs interact with squamous epithelium ex vivo. The results pave the way for various applications, e.g., biosensing, tissue engineering or targeted drug delivery of these highly biologically suitable nanoparticles.