Oxidative stress is an imbalance between the production of reactive oxygen species (ROS) and antioxidant mechanisms [
7] that can be explained as an increase in the generation of ROS or a decrease in antioxidants. A significant antioxidant found in animals, plants, and fungi is glutathione (GSH), which can halt losses caused by ROS. It is available in oxidized (GSSG) and reduced (GSH) forms. In usual healthy cases, most of the glutathione pool (about 90% of the total) is in a reduced state. An increased GSSG-to-GSH ratio indicates oxidative stress [
8]. ROS can be triggered through various mechanisms, for example: (i) interaction with oxidative organelles such as mitochondria, (ii) involvement with redox active proteins, (iii) the chemical reaction of surface groups or coating from the NPs in the acidic environment, and (iv) the activation of different signaling routes via interaction with cell surface receptors [
7,
9]. In contrast, such reactions do not occur in the presence of all NPs, such as cerium oxide (CeO
2). CeO
2 NPs do not cause the formation of ROS, and they display a preserving effect against ROS damage both in vitro and in vivo [
10,
11]. Research shows that vitamin-C-conjugated NPs protect cells from oxidative stress at micromolar concentrations, and they induce cell death at millimolar concentrations [
12]. The exact molecular target and chemical properties of oxidative stress, as well as the question of how it affects the modification of distinct biological procedures in cells subjected to engineered NPs (ENPs), have not yet been fully understood. Several studies postulate that reversible oxidative posttranslational modifications of protein cysteines via ROS and RNS show the basic mechanism of cell signaling that adjusts the protein functions of several cellular activities [
13,
14]. Protein S-glutathionylation (SSG) is a vital redox adjustment, altering apoptosis, mitochondrial metabolism, and transcription [
15]. These SSG alterations are controlled by physiological properties. They can be repaired by glutaredoxin (Grx) enzymes [
15,
16]. Site-specific profiling of SSG modifications at a proteome-wide scale can be achieved through quantitative redox proteomics [
17]. Using an SSG mechanism, Duan et al. assessed the modification of macrophage innate immune functions by ENPs via quantitative redox proteomics for the site-specific measurement of SSG alterations [
18]. Three ENPs (silicon oxide (SiO
x), Fe
3O
4, and cobalt oxide (II) (CoO)) were applied to stimulate disrupted macrophage function and cellular ROS, yielding low, moderate, and high propensity, respectively. SSG regulations indicate specific Cys residues and a wide range of redox-sensitive proteins corresponding to the total amount of cellular oxidative stress (CoO > Fe
3O
4 >> SiO
2). ENPs that generate moderate and serious ROS show different pathways in response to SSG. Pathways modify protein stability and translation representative of the ER stress response. Proteins in phagocytosis, however, are highly susceptible to SSG in the presence of Fe
3O
4 [
18]. ENPs trigger a subcytoxic degree of redox stress. ENP mitochondrial energetic pathways and classical stress responses are affected by SSG alternation moreso than redox stress caused by CoO.