The use of magnetic nanoparticles in biological applications is hampered by the lack of versatile methods to transfer them into aqueous solutions. Monolayer exchange using anionic octa(tetramethylammonium)−polyhedral oligomeric silsesquioxane provides individual particles that are soluble in aqueous environments and possess excellent stability in biologically relevant pH ranges and salt concentrations. In addition, this surface exchange reaction proved to be general in nature, allowing facile functionalization of a variety of magnetic nanoparticles.