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

Utilization of nanoparticles as innovative theranostic agent for various biomedical applications requires full control over the materials properties to dictate their interactions and effects within a biological environment. Owing to its versatile surface chemistry and high biocompatibility, nanodiamond (ND) represents an ideal platform paving the way for revolutionary treatments in healthcare. To ensure performance and safety of NDs, it is crucial that their properties and behavior remain unaffected upon administration, which embodies one of the main obstacles 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 nanodiamond (mND) 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 a different dipeptide, it is possible to carefully tailor the biocompatibility and cellular uptake of functionalized NDs. We reveal the biocompatibility of these functionalized NDs in biologically relevant 3D organotypic models (OTs) 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 biocompatible nanoparticles.