# Safe Functional Modified CuO Nanoparticles?
## 1 Introduction  
[PERSON] et al. [1] called safe-by-design 'a grand challenge of safe nanotechnology'. In this journal, [PERSON] and [PERSON] [2], discussing green nanotechnology, noted the importance of safer-by-design approaches as objects for future research. Reviews suggest that most of the research regarding safe(r)-by-design nanomaterials is in the field of nanomedicine, where the focus is on safety for humans in the use stage [3; 4; 5]. As to nanoparticles that can be applied outside the field of nanomedicine, there is now a substantial amount of research regarding safe(r)-by-design efforts based on modifications of CuO nanoparticles, which will be reviewed in Section 2. CuO nanoparticles are used as biocides, for instance in wood preservation and antifouling, and presumably also in agricultural fungicides [6; 7; 8; 9; 10]. The proposed applications of CuO nanoparticles regard catalysts [11; 12; 13], sensing [14; 15; 16], solar stills [17], solar collectors [18; 19] and additives in diesel fuels [20]. CuO nanoparticles are traditionally generated using methods from physics and inorganic chemistry. Approaches to synthesis include electrochemistry, sonochemistry, mechanochemistry and solvothermal and hydrothermal methods [15]. Nanoparticles generated by such methods will be considered here. It is possible to synthesize specific nanostructures, such as CuO nanorods, belts, fibers and flowers, but these will not be discussed. Recently, there has been an upsurge in the laboratory-scale biosynthetic generation of CuO nanoparticles, especially using plant extracts [21]. Such particles will be briefly referred to below. Hazards of CuO nanoparticles apply to their production, processing, use and waste stages. In a variety of organisms, including invertebrates, plants and mammalian species, hazard of such CuO nanoparticles have been linked to the release of Cu ions and the pro-oxidant activity associated with the induced generation of reactive oxygen species (ROS) [22; 23; 24; 25; 26; 27; 28; 29; 30; 31]. It may be noted, though, that [PERSON] et al. [6] have found that exposure of the tadpole _Xenopus laevis_ to low CuO nanoparticle concentrations positively affectedgrowth and metamorphosis, whereas, at higher concentrations, the impact on development was negative. The mechanism underlying this biphasic impact has not been clarified, but it has been reported that CuO nanoparticles may have an antioxidant effect by scavenging free radicals [32]. It has furthermore been documented by [PERSON] et al. [33] and [PERSON] et al. [34] that, dependent on morphology and concentration, several other metal oxide nanoparticles have an antioxidant effect, in which the scavenging of free radicals and the mimicking of antioxidant enzymes may be involved. [PERSON] et al. [35] studied manganese oxide nanoparticles that were predominantly antioxidant at low concentrations and predominantly pro-oxidant at higher concentrations. It may be that, similar to the manganese oxide nanoparticles studied by [PERSON] et al. [35], CuO nanoparticles may have a predominantly antioxidant effect at low nanoparticle concentrations. In the case of biosynthesized CuO nanoparticles, biogenic compounds with antioxidant activity might be present in the nanoparticles, enhancing the overall antioxidant activity of CuO nanoparticles [36; 37]. An antioxidant effect is relevant to the hazard of metal oxide nanoparticles, e.g., [33]. One safe-by-design option for nanoparticles that prevents exposure during their use, is their irreversible binding to large inorganic substrates, e.g., [38]. This option may be considered for CuO nanoparticles in terms of their application in sensors and regarding a part of their proposed applications in catalysis. When irreversible binding to large inorganic substrates is at variance with nanoparticle functionality, the modification of CuO nanoparticles may be considered. In two cases it has been claimed that modifications of Cu nanoparticles confer safety-by-design. [PERSON] et al. [39] studied CuO nanoparticles doped with Fe.