**5. Nano-Antioxidants**

Antioxidants have been accorded as effective therapeutic and prophylactic agents for various diseases. However, these antioxidants have received very limited success until now, as most of the antioxidants show low permeability, and are poorly soluble in water, demonstrate instability during storage and gastrointestinal degradation, which are some of their limitations [61]. The amalgamation of material sciences with nanotechnology has substantially improved and reduced the free radical synthesis during nanoparticle production in different areas and the nanoparticles synthesized for this purpose are regarded as nano-antioxidants [62,63]. Carbon nanotubes, metal and metal oxide nanoparticles and various types of polymer-loaded antioxidant nanoparticles, have been reported to exhibit antioxidant properties [63]. In the past few decades, various preparation protocols, such as emulsion/solvent evaporation, supercritical fluid technology, solvent displacement method, templating method and nanoprecipitation techniques, have been used for synthesizing nano-oxidants [63]. Some oxide nanoparticles can scavenge the reactive nitrogen and reactive oxygen species (RNS/ROS) and mimic the antioxidant molecule, due to their intrinsic physicochemical properties [64]. In the biomedical field, cerium oxide nanoparticles (CONPs) have gathered special attention for their multi-enzymatic scavenging of ROS and their regenerative abilities [65]. These CONPs have unique properties, like the coexistence in both oxidation states i.e., Ce3<sup>+</sup> and Ce4+, the ability to reversibly switch between both oxidation states and the reduction potential of ~1.52 V [66]. Cerium dioxide as a bulk crystal primarily contains Ce4<sup>+</sup>, but during its reduction to nano-size, substantially enhances the relative amount of Ce3<sup>+</sup>, therefore, leading to higher catalytic activity, in contrast to various biological processes and biological antioxidants [67,68]. Hirst et al. (2013) conducted an in vivo test on mice to assess the antioxidant potential of nanoceria, which were injected intravenously in the subject, and the result of the study revealed that nanoceria significantly decreased the lipoperoxidation after the three weeks, which indicates that CONPs are effective in treating oxidative stress [69]. Caputo et al. (2015) conducted a comparative study to assess the antioxidant potential between CONPs and NAC (N-acetyl-cysteine) and Trolox (soluble analogues of vitamin E) [70]. The results of this study revealed that NAC and Trolox reduced the oxidative 2- -7- -Dichlorofluorescein (DCF) signal triggered by irradiated TiO2 nanoparticles, but the antioxidant potential was significantly lower in comparison to CONPs. This result also highlights the stability of CONPs because of their auto-regenerative redox cycle, which allows them to surpass the challenges related to the stability of the antioxidants molecules.

On the other hand, synthetic polymeric NPs have emerged as the promising nano-drug delivery system, as they can encapsulate the therapeutic agent and progressively release the therapeutic compound at the target site. Poly-D, L-lactide (PLA) and poly (lactic-co-glycolic acid) (PLGA) are some examples of synthetic biodegradable polymers that have been approved safe by the European Medicine Agency (EMA) and U.S. Food and Drug Administration (FDA) for administration (Table 2).



Liposomes are also used for delivering the antioxidant agents to the target site. The amphiphilic and biocompatible nature of these liposomes allows them to load both hydrophilic and lipophilic compounds and favor the encapsulation of the water-soluble and water-insoluble antioxidant enzymes [79].

Furthermore, chitosan is the material predominantly used for synthesizing nanoparticles as a sole material or in amalgamation with another [80]. Chitosan shows mucoadhesive properties, which improves the targeted delivery in mucosal surfaces such as intestinal and nasal epithelium [81]. Curcumin encapsulated in nanocarrier and covered and stabilized with chitosan has also been developed and evaluated for free radical scavenging in comparison with free curcumin, and showed the protective effect of chitosan on the antioxidant activity of curcumin [82]. Pu et al. (2014) reported the encapsulation of curcumin antioxidant compounds within the nanocarrier and regulation of release of antioxidant compounds, by changing the pH and oxidative stress of inflamed tissues to increase the overproduction of RNS/ROS synthesized by lipopolysaccharide (LPS)-stimulated macrophage [83].
