**7. Challenges**

Apart from the widespread applications of metallic nanoparticles, owing to their size, chemical composition, shape, stability, functionalization, surface coating and purity, they also possess potential toxic effects [161]. Nanoparticles show characteristically distinct cellular uptake mechanisms, and also exhibit the ability to catalyze the synthesis of ROS, thus, leading to ROS associated toxic effects [162]. The size of the NPs is also known to affect the uptake of NPs and their distribution within the cell significantly, and it has been found that in NPs with the same dosage but having distinct sizes; the small-sized NPs are readily internalized within the cell than the large-sized NPs [163]. Moreover, it has been observed that the small-sized NPs possess relatively high reactivity, as they have a large surface area [164]. The size, surface charge and the material type of NPs determine the aggregating efficiency of MNPs, which further influences the internalization of NPs in the cell, and ultimately affects the NPs

associated toxicity [165]. A lot of research is being carried out at a global scale to evaluate the NP's associated toxic effects. Cho et al. (2009) found that polyethyleneglycol (PEG)-coated AuNPs triggers acute inflammation, as well as apoptosis, in the liver after intravenous injection, and also leads to the aggregation of the AuNPs in the cytoplasmic vesicles, liver and spleen [166]. There are numerous transition metals like copper (Cu), chromium (Cr), iron (Fe), silicon (Si) and vanadium (V), which are also involved in the generation of ROS via the Fenton reaction and the Haber-Weiss mechanism [167]. Apart from this, ZnONPs have also been reported to increase the cytotoxicity, due to the formation of ROS, which causes oxidative damage, and evoke the release of inflammatory mediators, thus, resulting in the senescence of phagocytic RAW264.7 cells and the transformation of BEAS-2B (human bronchial epithelial) cells [168]. These are some of the challenges associated with the use of metallic and metalloid NPs, and continuous efforts are being made to eliminate and overcome these challenges.
