The use of detonation nanodiamond (DND) for drug delivery and cell-imaging is grounded on its chemical functionalization, and the key task to be addressed is the capability to simplify the process steps, to reduce the process times and to maximize the drug/ligand uptake. The idea underlying the present research is to modulate the loading capability of DND by controlled modification of the surface organic groups. To this aim the DND samples are treated either by wet chemistry, using medium-strong reducing agents, or by tunable H-plasmas produced in a custom-designed MW-RF reactor. The affinity of the treated DND surfaces for drugs has been probed by conjugating the ciproten (5,7- dimethoxycoumarin), a natural antioxidant molecule, and by testing in vitro the feasibility to use coumarin vehicled by nanodiamond (C@DND) as chemioterapeutic drug. The methodologies developed to modify the DND surfaces are offering practical solutions to the still open problems related to DND-based systems for drug delivery applications.