Inorganic iron oxide nanoparticle cores as model systems for inorganic nanoparticles were coated with shells of amphiphilic polymers, to which organic fluorophores were linked with different conjugation chemistries, including 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) chemistry and two types of “click chemistry”. The nanoparticle-dye conjugates were exposed to different enzymes/enzyme mixtures in order to investigate potential enzymatic degradation of the fluorophore-modified polymer shell. The release of the dyes and polymer fragments upon enzymatic digestion was quantified by using fluorescence spectroscopy. The data indicate that enzymatic cleavage of the fluorophore-modified organic surface coating around the inorganic nanoparticles in fact depends on the used conjugation chemistry, together with the types of enzymes to which the nanoparticle-dye conjugates are exposed.