Potential of Nano-Antioxidants and Nanomedicine for Recovery from Neurological Disorders Linked to Long COVID Syndrome

Long-term neurological complications, persisting in patients who cannot fully recover several months after severe SARS-CoV-2 coronavirus infection, are referred to as neurological sequelae of the long COVID syndrome. Among the numerous clinical post-acute COVID-19 symptoms, neurological and psychiatric manifestations comprise prolonged fatigue, “brain fog”, memory deficits, headache, ageusia, anosmia, myalgias, cognitive impairments, anxiety, and depression lasting several months. Considering that neurons are highly vulnerable to inflammatory and oxidative stress damages following the overproduction of reactive oxygen species (ROS), neuroinflammation and oxidative stress have been suggested to dominate the pathophysiological mechanisms of the long COVID syndrome. It is emphasized that mitochondrial dysfunction and oxidative stress damages are crucial for the pathogenesis of neurodegenerative disorders. Importantly, antioxidant therapies have the potential to slow down and prevent disease progression. However, many antioxidant compounds display low bioavailability, instability, and transport to targeted tissues, limiting their clinical applications. Various nanocarrier types, e.g., liposomes, cubosomes, solid lipid nanoparticles, micelles, dendrimers, carbon-based nanostructures, nanoceria, and other inorganic nanoparticles, can be employed to enhance antioxidant bioavailability. Here, we highlight the potential of phytochemical antioxidants and other neuroprotective agents (curcumin, quercetin, vitamins C, E and D, melatonin, rosmarinic acid, N-acetylcysteine, and Ginkgo Biloba derivatives) in therapeutic strategies for neuroregeneration. A particular focus is given to the beneficial role of nanoparticle-mediated drug-delivery systems in addressing the challenges of antioxidants for managing and preventing neurological disorders as factors of long COVID sequelae.

The SARS-CoV-2 virus invades the CNS by binding to the angiotensin-converting enzyme-2 (ACE2) receptor, which is widely distributed in the epithelial cells of lungs and the endothelial cells of the blood-brain barrier (BBB) [19,20]. The neuroinvasive potential of the coronavirus is revealed by the provoked neuroinflammation and neuronal demyelination of the CNS, cellular apoptosis, metabolic imbalances, and various coagulopathies and endotheliopathies that induce hypoxic-ischemic neuronal injury or blood-brain barrier dysfunction [1,5,8,9,16,18].
Hyper-inflammation and oxidative stress have been suggested as the key factors underlying the pathophysiological pathways of long COVID [21][22][23] (Figure 1). It is recognized that the coronavirus infection compromises mitochondrial regulation and causes a decrease in adenosine triphosphate (ATP) synthesis and the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This contributes to the production of reactive oxygen species (ROS). Virus invasion also leads to inflammatory responses in the brain by triggering the release of cytokines, including interleukin (IL-10), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (INF-γ). This cascade goes a long way to further increase mitochondrial ROS production through the upregulation of mitochondrial genes and the modulation of the electron transport chain (ETC) [23][24][25][26].

Role of Antioxidants in Neuroprotection from Neurological Long COVID Sequelae
To address the challenges of the long COVID syndrome, the National Institute for Health and Care Excellence (NICE) has issued a diagnostic approach and treatment guidelines to promote the management of long COVID with a peculiar focus on neurological manifestations [46][47][48][49][50]. Even though more than 200,000 papers on COVID-19 have been published in less than three years, there is still a striking gap in the literature on specific treatment recommendations for neurological long COVID sequelae.
Here, we highlight some therapeutic agents that may significantly help to ameliorate long-term-COVID conditions. Amongst these are antioxidant compounds or agents endowed with antioxidant properties (Figure 3). They have demonstrated an improved prognosis of COVID-19 patients via different mechanisms, mainly by reducing inflammation [28,51]. In many cases, these compounds share multiple mechanisms of action, which may render them more efficient in exerting broad-spectrum protective effects. In a synergic fashion, their neuroprotective properties may be enhanced by complementation with antioxidants with different mechanisms of action. Most antioxidant compounds are molecules from natural sources or of dietary origin (nutraceuticals). In the latter case, a balanced diet and supplementation with proper nutrients can contribute to the prevention, treatment, and management of COVID-19 and its associated neurological sequelae. Pathway of SARS-CoV-2-induced neurological damages: (a) SARS-CoV-2 provokes the release of ROS, which leads to endoplasmic reticulum stress (ER) or oxidative stress that can damage lipids, proteins, and DNA biomolecules in the cells and can downregulate the expression of antioxidant proteins CAT, SOD, GPx, GSH, and the levels of uric acid and bilirubin as causative factors for neuronal cell death. (b) Immune response to inflammation triggers inflammatory markers involving cytokines and chemokines that can initiate cytokine storm syndrome. (c) Infected leukocytes can infect the central nervous system by crossing and disrupting the BBB. (d) SARS-CoV-2 enters the CNS through the olfactory epithelium, which expresses the ACE2 receptor. The resulting infection causes neuronal death and olfactory dysfunction. Up and down arrows indicate the upregulation and downregulation of biomarkers, respectively (Created with BioRender).

Role of Antioxidants in Neuroprotection from Neurological Long COVID Sequelae
To address the challenges of the long COVID syndrome, the National Institute for Health and Care Excellence (NICE) has issued a diagnostic approach and treatment guidelines to promote the management of long COVID with a peculiar focus on neurological manifestations [46][47][48][49][50]. Even though more than 200,000 papers on COVID-19 have been published in less than three years, there is still a striking gap in the literature on specific treatment recommendations for neurological long COVID sequelae.
Here, we highlight some therapeutic agents that may significantly help to ameliorate long-term-COVID conditions. Amongst these are antioxidant compounds or agents endowed with antioxidant properties (Figure 3). They have demonstrated an improved prognosis of COVID-19 patients via different mechanisms, mainly by reducing inflammation [28,51]. In many cases, these compounds share multiple mechanisms of action, which may render them more efficient in exerting broad-spectrum protective effects. In a synergic fashion, their neuroprotective properties may be enhanced by complementation with antioxidants with different mechanisms of action. Most antioxidant compounds are molecules from natural sources or of dietary origin (nutraceuticals). In the latter case, a balanced diet and supplementation with proper nutrients can contribute to the prevention, treatment, and management of COVID-19 and its associated neurological sequelae. ntioxidants 2023, 12, x FOR PEER REVIEW 5 of 30 Figure 3. Examples of antioxidant agents with neuroprotective properties that have been proven to play a role in preventive and/or adjuvant therapies for patients infected with COVID-19. Quercetin is presented as an example of flavonoids; ginkgolide B, as an example of terpenoid, derivative of ginkgo biloba; and curcumin, as an example of curcuminoid.

Nanodelivery Systems for Development of Antioxidant-Based Nanomedicines against the Neurological Sequelae of SARS-CoV-2
Nanomedicine-based therapies against the neurological sequelae of long COVID will require developing nanoscale delivery systems for the efficient use of antioxidants. In terms of drug delivery, antioxidants display several limitations, including (i) low permeability into the CNS due to the presence of physiological barriers such as the BBB or the spinal-blood barrier (SBB) [52]; (ii) low bioavailability associated with insolubility or instability [53]; (iii) chemical and physical barriers in the gut such as the acidic pH of the stomach, the intestinal mucosal lining, and the selectively permeable membranes of enterocytes [54]; and (iv) rapid metabolism [55]. Significant efforts have been made to improve the efficacy of antioxidant agents using various drug-delivery approaches. Figure 4 shows examples of nanocarriers fabricated with natural or synthetic compounds, e.g., lipids, polymers, or inorganic materials. In general, formulating antioxidants in nanocarriers can enhance their efficacy due to a higher stability upon encapsulation and an improved transport to the CNS compared with free antioxidant compounds.

Nanoparticle Types as Antioxidant Carriers
Nanoparticles (NPs) can be categorized as (i) purely organic compound NPs or (ii) inorganic NPs, based on the elements that built up their structure ( Figure 4) [56]. The majority of organic materials are biocompatible, biodegradable, and non-toxic. However, inorganic materials are characterized by their smaller particle size, stability, controlled tunability, higher permeability, efficient antigen loadings, and triggered-release profile.
Organic molecule-based nanosystems developed as delivery vehicles of antioxidants include liposomes, micelles, and polymeric nanoparticles. Liposomes, for example, are lipid-based nanomaterials that consist of an aqueous core surrounded by a phospholipid bilayer. Depending on the hydrophobic/hydrophilic balance and molecular shapes,

Nanodelivery Systems for Development of Antioxidant-Based Nanomedicines against the Neurological Sequelae of SARS-CoV-2
Nanomedicine-based therapies against the neurological sequelae of long COVID will require developing nanoscale delivery systems for the efficient use of antioxidants. In terms of drug delivery, antioxidants display several limitations, including (i) low permeability into the CNS due to the presence of physiological barriers such as the BBB or the spinal-blood barrier (SBB) [52]; (ii) low bioavailability associated with insolubility or instability [53]; (iii) chemical and physical barriers in the gut such as the acidic pH of the stomach, the intestinal mucosal lining, and the selectively permeable membranes of enterocytes [54]; and (iv) rapid metabolism [55]. Significant efforts have been made to improve the efficacy of antioxidant agents using various drug-delivery approaches. Figure 4 shows examples of nanocarriers fabricated with natural or synthetic compounds, e.g., lipids, polymers, or inorganic materials. In general, formulating antioxidants in nanocarriers can enhance their efficacy due to a higher stability upon encapsulation and an improved transport to the CNS compared with free antioxidant compounds.   Examples of organic delivery vehicles include liposomes, cubosomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Examples of inorganic nanoparticles include nanoceria, mesoporous silica nanoparticles, and iron oxide NPs. Carbon-based materials, which lack carbonhydrogen bonds typical of organic compounds, include various types of nanostructures (e.g., carbon nanotubes, graphene nanosheets, and fullerenes). The properties of the different nanocarriers are described in the text.
Solid lipid nanoparticles (SLNs) are widely known transporters of chemotherapeutic agents to the CNS [37]. These matrix-type lipid particles, usually consisting of fatty acids or mono-, di-, or triglycerides, remain with a solid core at body temperature. Cubosomes are liquid crystalline nanostructures created from cubic-phase-forming lipids, such as monoolein and phytantriol [29,35,38], which have the unique ability to disperse into nanoparticles that are stable upon dilution [57][58][59]. Liposomes and cubosomes can encapsulate hydrophobic drugs in the lipid bilayer membranes and hydrophilic compounds in the aqueous compartments [29,35,37].
Inorganic nanoparticles are primarily known for their use in diagnostic and theranostic applications. Iron oxide nanoparticles (IONPs) are one type of inorganic NPs that has been extensively employed for therapeutic and diagnostic imaging since the 1960s. Gold nanoparticles (AuNPs) have been widely studied due to their biocompatibility and the ease of controlling their size distribution and shape. AuNPs can take a variety of shapes, including spheres, nanorods, and cubes, among others. Other inorganic na- Examples of organic delivery vehicles include liposomes, cubosomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Examples of inorganic nanoparticles include nanoceria, mesoporous silica nanoparticles, and iron oxide NPs. Carbon-based materials, which lack carbon-hydrogen bonds typical of organic compounds, include various types of nanostructures (e.g., carbon nanotubes, graphene nanosheets, and fullerenes). The properties of the different nanocarriers are described in the text.

Nanoparticle Types as Antioxidant Carriers
Nanoparticles (NPs) can be categorized as (i) purely organic compound NPs or (ii) inorganic NPs, based on the elements that built up their structure ( Figure 4) [56]. The majority of organic materials are biocompatible, biodegradable, and non-toxic. However, inorganic materials are characterized by their smaller particle size, stability, controlled tunability, higher permeability, efficient antigen loadings, and triggered-release profile.
Organic molecule-based nanosystems developed as delivery vehicles of antioxidants include liposomes, micelles, and polymeric nanoparticles. Liposomes, for example, are lipid-based nanomaterials that consist of an aqueous core surrounded by a phospholipid bilayer. Depending on the hydrophobic/hydrophilic balance and molecular shapes, the amphiphilic structures enable the formation of thermodynamically stable vesicles [57]. Amphiphilic molecules can also self-assemble to form micelles, which contain hydrophilic (polar) headgroups and hydrophobic (nonpolar) tails. In aqueous media, micelles are typically assembled with the polar part facing the exterior and the nonpolar region constituting the core.
Solid lipid nanoparticles (SLNs) are widely known transporters of chemotherapeutic agents to the CNS [37]. These matrix-type lipid particles, usually consisting of fatty acids or mono-, di-, or triglycerides, remain with a solid core at body temperature. Cubosomes are liquid crystalline nanostructures created from cubic-phase-forming lipids, such as monoolein and phytantriol [29,35,38], which have the unique ability to disperse into nanoparticles that are stable upon dilution [57][58][59]. Liposomes and cubosomes can encapsulate hydrophobic drugs in the lipid bilayer membranes and hydrophilic compounds in the aqueous compartments [29,35,37].
Inorganic nanoparticles are primarily known for their use in diagnostic and theranostic applications. Iron oxide nanoparticles (IONPs) are one type of inorganic NPs that has been extensively employed for therapeutic and diagnostic imaging since the 1960s. Gold nanoparticles (AuNPs) have been widely studied due to their biocompatibility and the ease of controlling their size distribution and shape. AuNPs can take a variety of shapes, including spheres, nanorods, and cubes, among others. Other inorganic nanoparticles are nanoceria, silica nanoparticles (SiNPs), particularly mesoporous silica nanoparticles (MSNPs), and iron oxide NPs [63][64][65] (Figure 4).

Curcumin-Loaded Nanoparticles
In light of the COVID-19 pandemic, at least three types of curcumin-based nanotechnological products are available on the market in the form of liposomes (Lipocurc™), polymeric nanoparticles (Nanocurc™), or nanomicelles (Sinacurcumin ® ) [66]. Sinacurcumin ® (40 mg, four capsules daily for 14 days) has been shown to reduce mortality by decreasing the cytokine storm [67]. Nanoparticulate formulations (e.g., curcumin-loaded Se-PLGA nanospheres) have proven their potency to improve cognition, inhibit the aggregation of Aβ, and reduce depressive-like behaviour and oxidative stress in AD models [68].
Curcumin is one of the most-marketed antioxidant compounds with a promising nutraceutical profile and a safety tolerated dose of up to 12 g/day [29,66,69,70]. Zahedipour et al. have emphasized the remarkable effects of curcumin in the treatment of COVID-19 [70]. The pleiotropic effects of the phytochemical against viruses are related to its ability to interact with various molecular targets by modulating various signaling cascades, which are relevant for virus replication, by attenuating NF-κB and PI3K/Akt signaling as well as regulating the expression of both pro-and anti-inflammatory proteins such as IL-6, IL-8, IL-10, and COX-2. In this way, curcumin impacts the apoptosis of polymorphonuclear neutrophil cells (PMNs), an abundant immune-system cell type. In an animal model of stroke, Jiang et al. have shown that curcumin treatments result in an essential total decrease in the infarct volume, an improved neurological deficit, and a reduced mortality in a dose-dependent manner [71].
In animal models of depression, curcumin has been found to normalize the levels of dopamine, noradrenaline, and 5-hydroxyindoleacetic acid in the frontal cortex of rats. This outcome indicates that curcumin may act as a potent antioxidant against depression [72,73]. Regarding anosmia and ageusia, a case series has revealed a rapid and effective recovery of taste and smell in two subjects infected with COVID-19 following the ingestion of a 1000 mg dosage of a turmeric supplement that contained 95% curcuminoids [74].
An intriguing study showed that curcumin-loaded insulin d-α-tocopherol succinate (INVITE) micelles enhanced the ability of mesenchymal stromal cells (MSCs) to boost neuronal protection and replace dead motor neurons in the spinal cord. This groundbreaking strategy has been demonstrated to have considerable potential for the treatment of ALS [75]. The effects of curcumin-loaded nanoparticles on the neurological effects of SARS-CoV-2 are revealed in Figure 5. display library as a replacement for the protein transferrin in drug delivery to the brain [79,80]. In a related study, Yin et al. created sialic acid (SA)-modified selenium (Se) nanoparticles conjugated with the B6 peptide (B6-SA-SeNPs), which had high permeability across the BBB and successfully prevented Aβ peptides from aggregating and disaggregated the preformed Aβ fibrils into non-toxic amorphous oligomers [81].

Curcumin Nanoconjugates
Peptide (B6)-conjugated curcumin-loaded PLGA-PEG-B6 nanoparticles have been established to decrease hippocampal Aβ burden in APP/PS1 mice as revealed by immunofluorescence and immunohistochemistry results [76]. Drug distribution into the CNS is essentially hampered by the relative impermeability of the BBB due to the tight junctions between cerebral microvascular endothelial cells, which also play a significant role in brain homeostasis. Receptors with high endothelial cell expression, including the insulin, transferrin, and integrin receptors, are of particular interest for receptor-mediated transport (RMT) because of their ability to increase the efficiency and specificity of brain delivery [77]. The transferrin receptor (TfR), one of these different receptors, has been the subject of much research for BBB targeting during the past ten years [78]. Nevertheless, further developments are still needed to overcome drawbacks related to immunological responses, NP synthesis methods, and NP stability. The B6 peptide (CGHKAKGPRK), a promising targeting ligand of TfR, has been produced from a phage display library as a replacement for the protein transferrin in drug delivery to the brain [79,80].
In a related study, Yin et al. created sialic acid (SA)-modified selenium (Se) nanoparticles conjugated with the B6 peptide (B6-SA-SeNPs), which had high permeability across the BBB and successfully prevented Aβ peptides from aggregating and disaggregated the preformed Aβ fibrils into non-toxic amorphous oligomers [81]. Figure 6 shows the reduction in the Aβ plaque deposition in nanoparticle-treated APP/PS1 animals compared with wild-type mice. According to these findings, PLGA-PEG-B6/Cur nanoparticles may be potentially effective for AD therapies when focusing on Aβ pathophysiology in neurological and neuropsychiatric manifestations [76].

NAC-Loaded Nanoparticles
N-acetylcysteine (NAC) is a sulfhydryl-containing compound with mucolytic properties ( Figure 3). It functions as a precursor of the antioxidant glutathione and the amino acid L-cysteine [82,83]. The ability of NAC to block certain signaling pathways, such as the c-Jun N-terminal kinase, p38 MAP kinase, SAPK/JNK, and c-Fos pathways, as well as NF-κB, and to regulate cytokine synthesis (anti/pro-inflammatory effect) and

NAC-Loaded Nanoparticles
N-acetylcysteine (NAC) is a sulfhydryl-containing compound with mucolytic properties ( Figure 3). It functions as a precursor of the antioxidant glutathione and the amino acid L-cysteine [82,83]. The ability of NAC to block certain signaling pathways, such as the c-Jun N-terminal kinase, p38 MAP kinase, SAPK/JNK, and c-Fos pathways, as well as NF-κB, and to regulate cytokine synthesis (anti/pro-inflammatory effect) and antiapoptotic genes is also supported by a number of works [84][85][86].
In Parkinson's disease, thiol-containing compounds such as NAC exert a protective action by inhibiting dopamine-induced cell death [87]. NAC has partially protected the mouse brain against cadmium-induced neuronal apoptosis by inhibiting the ROSdependent activation of the Akt/mammalian target of the rapamycin (mTOR) signaling pathway [87]. NAC is a potential candidate for treating neuropathic pain, which has occurred in up to 2.3% of hospitalized patients with COVID-19 [88], as well as ME/CFS, by providing neuroprotection against oxidative stress and replenishing the cortical GSH reserves [89,90]. In healthy BV2 murine microglia, hydroxyl-terminated polyamidoamine dendrimers containing the antioxidant NAC reduced oxidative stress compared with free N-acetylcysteine [91].
A dendrimer-based therapy (D-NAC) for neuroinflammation and cerebral palsy (CP) was developed using NAC as a drug [92]. In this work, newborn babies with CP were randomly administered with NAC at concentrations of 10 mg/kg (NAC_10), 100 mg/kg (NAC_100), D-NAC of 1 mg/kg (D-NAC_1), D-NAC of 10 mg/kg (DNAC_10), dendrimer alone (control), or PBS (negative control). Confocal microscopy results (Figure 7) showed a decrease in myelin basic protein (MBP) staining in the corona radiata, internal capsule, and external capsule following day 5 of life in endotoxin kits treated with PBS compared with healthy controls. A significant increase in myelin staining equivalent to the expression levels of healthy controls was seen in the kits treated with D-NAC at 10 mg/kg (D-NAC_10). In contrast, free antioxidants at a concentration of even 100 mg/kg (NAC_100) were less effective than D-NAC_10. Markers of oxidative injury in the brain's periventricular region (PVR) were used to identify oxidative injury and inflammation. After therapy, the amounts of 8-hydroxyguanosine (8-OHG) and GSH were assessed in healthy and CP rabbits. The treatment of the CP kits with D-NAC 1, D-NAC 10, and the highest dose of free medication (NAC 100) resulted in a rise in the GSH levels as compared with those of the healthy control kits. However, treatment with NAC_10 and dendrimer alone had no impact. This fact suggests that NAC is released from the brain's dendrimer conjugate. Even at the highest dose, D-NAC 10 significantly decreased the levels of 8-hydroxyguanosine (8-OHG), an early and sensitive marker for RNA oxidation in various neurodegenerative diseases [92]. The treatment with D-NAC (10 mg/kg) nanosystem significantly enhanced the number of neurons as compared with the healthy controls.
Antioxidants 2023, 12, x FOR PEER REVIEW 10 of 28 dendrimer alone (control), or PBS (negative control). Confocal microscopy results (Figure 7) showed a decrease in myelin basic protein (MBP) staining in the corona radiata, internal capsule, and external capsule following day 5 of life in endotoxin kits treated with PBS compared with healthy controls. A significant increase in myelin staining equivalent to the expression levels of healthy controls was seen in the kits treated with D-NAC at 10 mg/kg (D-NAC_10). In contrast, free antioxidants at a concentration of even 100 mg/kg (NAC_100) were less effective than D-NAC_10. Markers of oxidative injury in the brain's periventricular region (PVR) were used to identify oxidative injury and inflammation. After therapy, the amounts of 8-hydroxyguanosine (8-OHG) and GSH were assessed in healthy and CP rabbits. The treatment of the CP kits with D-NAC 1, D-NAC 10, and the highest dose of free medication (NAC 100) resulted in a rise in the GSH levels as compared with those of the healthy control kits. However, treatment with NAC_10 and dendrimer alone had no impact. This fact suggests that NAC is released from the brain's dendrimer conjugate. Even at the highest dose, D-NAC 10 significantly decreased the levels of 8-hydroxyguanosine (8-OHG), an early and sensitive marker for RNA oxidation in various neurodegenerative diseases [92]. The treatment with D-NAC (10 mg/kg) nanosystem significantly enhanced the number of neurons as compared with the healthy controls.

Taxifolin Nanocomplexes
Taxifolin (TAX: 3,3 ,4 ,5,7-pentahydroxy flavanone or dihydroquercetin) is a vital bioflavonoid polyphenolic antioxidant commonly found in fruits, vegetable oils, red wine, tea, Siberian larch, and onions. In terms of the chemical structure of the compound, the distribution of the hydroxyl groups among the three flavonoid rings (A, B, and C) is the same for taxifolin and quercetin. However, the two molecules differ in the presence or absence of a C-2 or C-3 double bond in the C-ring. Other derivatives of taxifolin include neoastilbin, astilbin, isoengeletin, isoastilbin, engeletin, taxifolin 7-O-glucoside, taxifolin 3-O-glucoside, taxifolin-7-O-rhamnopyranosid and taxifolin-3-O-rhamnopyranoside [93]. Taxifolin and its derivatives have shown to offer pharmacological benefits, including antioxidant, anti-inflammatory, antiviral, antibacterial, and enzyme-inhibitory properties. For instance, taxifolin exhibits an immediate neuroprotective effect, principally by decreasing the generation of ROS in the inhibitory population of GABA neurons. Furthermore, taxifolin can affect gene expression, which modulates cell survival and death. When administered at doses of 0.1 and 1.0 g/kg, taxifolin reduced infarction by 42% ± 7% and 62% ± 6%, respectively, in a rat ischemia-reperfusion (I/R) model. This was followed by a significant reduction in adduct formation of malondialdehyde and nitrotyrosine, two markers for oxidative tissue damage [94]. In a concurrent treatment, taxifolin and cilostazol synergistically inhibited amyloidogenesis by suppressing P-JAK2/P-STAT3-coupled NF-κB-linked BACE1 expression via the upregulation of SIRT1 in activated N2a Swe cells geared towards the intervention of AD [95,96].
Targeted delivery has been realized by nanocomplexes of selenium nanoparticles (SeNPs) with taxifolin (Se-TAX). In a recent work (Figure 8), Varlamova et al. developed selenium-taxifolin nanocomplexes to reduce ROS in neurons and astrocytes exposed to exogenous H 2 O 2 under ischemia-like circumstances [97]. This mechanism was demonstrated by activating certain antioxidant enzymes and inhibiting ROS-generating systems during OGD/reoxygenation. While free TAX molecules and "naked" SeNPs were less efficient in controlling the cellular redox state, Se-TAX decreased the concentration of cytosolic Ca 2+ ([Ca 2+ ]i) rise and hyperexcitation. The nanocomplex activated protective genes while simul-taneously suppressing the production of pro-inflammatory and proapoptotic proteins [97]. There is expanding research towards a better understanding of the role of calcium during viral infections, particularly in SARS-CoV-2. In this direction, the suppression of calcium transport across membranes and inside cells is a perspective target site that may alter the SARS-CoV-2 infection and potentially benefit severe COVID-19 courses [98]. Given these data (Figure 8), it has been inferred that the Se-TAX nanocomplex controls Ca 2+ dynamics and has anti-apoptotic properties [97].
Debnath et al. have demonstrated that nano-quercetin could exhibit an antiamyloidogenic activity at low quercetin concentrations, thereby preventing polyglutamine aggregation in a cell model of Huntington's disease [105]. It has been established that COVID-19 causes a disruption of the cholinergic system by binding to nicotinic ace-
Debnath et al. have demonstrated that nano-quercetin could exhibit an anti-amyloidogenic activity at low quercetin concentrations, thereby preventing polyglutamine aggregation in a cell model of Huntington's disease [105]. It has been established that COVID-19 causes a disruption of the cholinergic system by binding to nicotinic acetylcholine receptors (nAChRs), which results in a change in acetylcholine activity [106]. In this regard, the established protective role of quercetin and rutin against scopolamine-induced cognitive impairment in zebrafish appears to be promising in the enhancement of cholinergic neurotransmission [107]. Accordingly, Palle and colleagues showed that quercetin nanoparticles (NQCs) significantly reduced MDA and AchE levels while increasing CAT and GSH in a scopolamine-induced rat model of amnesia, demonstrating that it has an activity similar to that of an acetylcholinesterase inhibitor such as rivastigmine [108]. In a separate study, the co-encapsulation of epigallocatechin-3-gallate and acetyl acid (EGCG/AA NPs), which was orally administered to an APPswe/PS1dE9 mice model for Alzheimer's disease, led to an upregulation of synaptophysin (SYP) and influenced neuroinflammation, Aβ plaque burden, and the cortical levels of both soluble and insoluble Aβ  peptides, leading to an improvement in learning and memory [109]. Moreover, it has been reported that 4-hydroxyisophthalic acid (4-HIA) encapsulated PLGA-NPs significantly decreased the cytotoxicity of H 2 O 2 in PC12 cells when compared with non-encapsulated 4-HIA.
Yang et al. have demonstrated the beneficial effect of PLGA-PEG-Fucoxanthin nanoparticles in improving cognitive performance and transport through the CNS [110]. In an animal model of AD, resveratrol-loaded NPs decreased the levels of matrix metalloproteinase-9 (MMP-9) in cerebrospinal fluid, highlighting that resveratrol limits brain permeability, the infiltration of leukocytes, and other inflammatory agents. Resveratrol presents a therapeutic interest because it modulates neuroinflammation and induces adaptive immunity [111].

Ceria Oxide Nanoparticles
Ceria nanoparticles have been broadly studied as nanoscale antioxidant systems [112]. An example is given in Figure 9. Ceria nanoparticles can mimic the function of the antioxidant enzymes SOD and CAT. In redox processes, the cerium species transforms between two possible valence states of +4 (oxidized) and +3 (reduced) [113,114]. Cerium oxide NPs with a crystalline fluorite-type lattice structure display oxygen vacancies that result from the loss of oxygen and its electrons. Thus, in addition to the ionic state change from Ce 3+ to Ce 4+ , the nanoparticle's stoichiometry may also switch from CeO 2 to CeO 2−x [115]. As a result, CeONPs can interact with various free radicals and detoxify their harmful action based on modifications in the redox state and oxygen vacancies.
In recent years, in vivo and ex vivo models have been used to assess the efficacy of nanoceria using an electrochemical biosensor based on cytochrome C [116]. In particular, it has been demonstrated that cerium oxide nanoparticles with a diameter of about 15 nm exhibit a SOD-like activity equivalent to 527 U of SOD for each 1 µg/mL nanoceria, being able to lower superoxide levels in a mice brain slice [116]. By using mouse hippocampus brain slices as an ex vivo model of ischemia, Estevez et al. conducted another interesting study that demonstrated how cerium oxide nanoparticles could lower cell death levels by 50% [117]. For the treatment of neurotrauma, Yan et al. fabricated a nanozyme based on Pt/CeO 2 with effective catalytic activity. In vivo tests have shown that these species can accelerate healing and lessen neuroinflammation [118].
Additionally, CeONPs can regenerate their redox-active matrix, enabling repeated freeradical interactions, thanks to the lattice structure and simplicity of electronic conversions with other ionic species at the quantum level, allowing repetitive elimination of ROS [119].
Ceria nanoparticles have also shown a variety of therapeutic potentials for neuroand cardio-protection. Due to their high surface-to-volume ratio, small ceria nanoparticles (<5 nm), particularly, have shown improved therapeutic effectiveness. Kim et al. demon-strated that 3 nm ceria nanoparticles might protect the brain against ischemic stroke in rats [120].
In another work, Kwon et al. successfully synthesized conjugate triphenylphosphonium ceria nanoparticles (TPP-ceria NPs) [119]. They demonstrated effectiveness by localizing to mitochondria and preventing neuronal degeneration in a 5XFAD transgenic mouse model of Alzheimer's disease. In addition, TPP-ceria NPs also prevented reactive gliosis and morphological mitochondrial damage in mice [119].
Antioxidants 2023, 12, x FOR PEER REVIEW 14 of 30 Figure 9. Ceria nanoparticles for neuroprotection against stroke and BBB disruption. E-A/P-CeO2 and A/P-CeO2, ceria nanoparticles loaded with or without edaravone and modified with Angiopep-2 (ANG) and polyethylene glycol (PEG) on their surface; P-CeO2, ceria NPs decorated with PEG. (A) Schematic representation of the Angiopep-2 (ANG-targeting) of lipoprotein receptorrelated peptide (LRP) on the brain capillary endothelial cells (BCECs) that promote E-A/P-CeO2 crossing the BBB into brain tissue for the treatment of stroke. (B) Cerebral uptake of ceria nanoparticles was conducted on healthy rats whose BBB was complete. ICP-OES was used to measure the concentrations of ceria nanoparticles in brain tissue following intravenous injection. E-A/P-CeO2 nanoparticles were successfully carried across the BBB into the brain by an ANG-targeting and LRP-receptor-driven transcytosis mechanism in vivo. The results in Panel B demonstrate the accumulation of ceria NPs in the brain region within 24 h compared with P-CeO2 (* p < 0.05). (C) A model of stroke, middle cerebral artery occlusion (MCAO), was injected with different concentrations of ceria nanoparticles. Cerebral infarct volume was measured after 24 h by triphenyl tetrazolium chloride (TTC) staining. The normal stained tissue is red, and the unstained infarction is white. The result shows a high infarct volume of the control group of saline injection by 45.6 ± 4.8%. In contrast, treatment with E-A/P-CeO2 caused a decrease in infarction up to 15.0 ± 4.1% at an optimal concentration of 0.6 mg/kg in a dose-dependent manner. The neuroprotective effect of ceria nanoparticles indicates that E-A/P-CeO2 is more potent than A/P-CeO2 and P-CeO2, suggesting that edaravone attenuates ROS scavenging coupled with a targeted effect, thanks to the ceria core system which enhanced the antioxidant potency for improved treatment in vivo. Adapted with permission from [112]. Copyright {2018} American Chemical Society.
In recent years, in vivo and ex vivo models have been used to assess the efficacy of nanoceria using an electrochemical biosensor based on cytochrome C [116]. In particular, it has been demonstrated that cerium oxide nanoparticles with a diameter of about 15 nm exhibit a SOD-like activity equivalent to 527 U of SOD for each 1 μg/mL nanoceria, being able to lower superoxide levels in a mice brain slice [116]. By using mouse hippocampus brain slices as an ex vivo model of ischemia, Estevez et al. conducted another in- Figure 9. Ceria nanoparticles for neuroprotection against stroke and BBB disruption. E-A/P-CeO 2 and A/P-CeO 2 , ceria nanoparticles loaded with or without edaravone and modified with Angiopep-2 (ANG) and polyethylene glycol (PEG) on their surface; P-CeO 2 , ceria NPs decorated with PEG. (A) Schematic representation of the Angiopep-2 (ANG-targeting) of lipoprotein receptor-related peptide (LRP) on the brain capillary endothelial cells (BCECs) that promote E-A/P-CeO 2 crossing the BBB into brain tissue for the treatment of stroke. (B) Cerebral uptake of ceria nanoparticles was conducted on healthy rats whose BBB was complete. ICP-OES was used to measure the concentrations of ceria nanoparticles in brain tissue following intravenous injection. E-A/P-CeO 2 nanoparticles were successfully carried across the BBB into the brain by an ANG-targeting and LRP-receptor-driven transcytosis mechanism in vivo. The results in Panel B demonstrate the accumulation of ceria NPs in the brain region within 24 h compared with P-CeO 2 (* p < 0.05). (C) A model of stroke, middle cerebral artery occlusion (MCAO), was injected with different concentrations of ceria nanoparticles. Cerebral infarct volume was measured after 24 h by triphenyl tetrazolium chloride (TTC) staining. The normal stained tissue is red, and the unstained infarction is white. The result shows a high infarct volume of the control group of saline injection by 45.6 ± 4.8%. In contrast, treatment with E-A/P-CeO 2 caused a decrease in infarction up to 15.0 ± 4.1% at an optimal concentration of 0.6 mg/kg in a dose-dependent manner. The neuroprotective effect of ceria nanoparticles indicates that E-A/P-CeO 2 is more potent than A/P-CeO 2 and P-CeO 2 , suggesting that edaravone attenuates ROS scavenging coupled with a targeted effect, thanks to the ceria core system which enhanced the antioxidant potency for improved treatment in vivo. Adapted with permission from [112]. Copyright {2018} American Chemical Society.

Iron Oxide Nanoparticles in Regenerative Treatments
It has been suggested that iron oxide NPs may ameliorate neurodegeneration by mimicking the CAT activity and decomposing ROS [121,122]. Considering that significant microglial activation occurs prior to the creation of tangles in neurodegenerative tauopathies, reducing tau's ability to trigger this activation has been demonstrated to slow the development of the pathology [121,123]. Glat et al. have shown that utilizing fibrin γ 377−395 peptide conjugated to iron oxide (γ-Fe 2 O 3 ) nanoparticles, with a diameter of 21 ± 3.5 nm, specifically, inhibits microglial cells in rTg4510 tau-mutant mice. The number of neurons with hyperphosphorylated tau and tangles was significantly reduced compared with untreated animals [124].
Other studies have addressed the impact of magnetic nanoparticles on Aβ fibrillation. Specific surface-coated superparamagnetic iron oxide nanoparticles (SPIONs) can interact with amyloid-beta (Aβ) and other amyloidogenic proteins. Moreover, in a magnetic field, SPIONs may be transported to the target tissue and may also be impacted by the applied field. It has been reported that the Aβ fibrillation process is suppressed at lower concentrations of nanoparticles and accelerates in the presence of a magnetic field and high concentrations of nanoparticles [125].
As a prospective treatment for neurodegenerative disorders, Katebi et al. demonstrated that combining nerve growth factor (NGF), quercetin, and superparamagnetic IONPs boosted neurite outgrowth and improved neurite branching in PC12 cells [126]. Consistent with these data, Chung et al. showed that the therapeutic effects of human mesenchymal stem cells (hMSCs) in a mouse model of PD, induced by a local injection of 6-OHDA, may be enhanced by dextran-coated iron oxide nanoparticles (Dex-IO NPs) [127]. In situ analyses have revealed that Dex-IO NPs may enhance the rescue impact of hMSCs on host DA neuron loss. Moreover, the data have shown that Dex-IO NPs can augment the ability of hMSCs to migrate toward lesioned DA neurons and drive hMSCs to differentiate into DA-like neurons at the disease site [127]. IONPs are also extensively explored in diagnostics and the treatment of neurodegenerative diseases, including AD, PD, and ALS. They are used as drug carriers and MRI contrast agents in AD, allowing the development of a multifaceted approach for targeting, diagnosing, and treating CNS disorders [121,128].

Manganese-Based Nano-Antioxidants
Aside from selenium, manganese (Mn) is another micronutrient that plays a crucial role in brain function because it can pass both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCB). Furthermore, Mn 2+ ions typically concentrate in the mitochondria of brain cells through divalent metal transporters. Manganese oxides have applications in the targeted imaging of neurodegenerative disorders [129]. Among the many 3D-transition-metal oxides, manganese oxides, such as MnO, Mn 2 O 3 , Mn 3 O 4 , Mn 5 O 8 , and MnO 2 , have attracted particular interest due to their wide range of structural and compositional variations [130,131]. Mn-oxide nanoparticles with good physicochemical properties hold a promise for sustainable nanotechnology developments. In particular, MnO 2 has been explored for its ability to act as a nanoreactor in scavenging ROS [132,133]. In an acidic environment, MnO 2 nanoparticles have a natural peroxidase-like activity that may break down H 2 O 2 into water (H 2 O), oxygen (O 2 ), and manganese ions (Mn 2+ ) [134]. Some researchers have argued that MnO 2 particles could occasionally increase oxidative stress rather than decrease it. Therefore, combining them with nanotechnology-based systems may aid in better controlling their release and toxicity, providing protection for cells and enhancing their distribution to the target tissues [135].
Kuthati et al. have reported that intrathecal treatment by manganese oxide nanoparticles (MONPs) dramatically reduced mechanical allodynia and the expression of COX-2, a crucial mediator of chronic and inflammatory pain in the spinal dorsal horns of PSNT rats [136]. In parallel, Singh and colleagues have demonstrated that the multienzyme mimic, Mn 3 O 4 nanoparticles, provides exceptional protection to biomolecules against ROSmediated protein oxidation, lipid peroxidation, and DNA damage, preventing cells from suffering oxidative damage [137]. In a separate study, Mn 3 O 4 nanozymes demonstrated superiority to CeO 2 nanozymes in ROS elimination. The effectiveness in vivo was evidenced by the prevention of ROS-induced ear inflammation in live mice [138]. Under hypoxic conditions, antioxidant manganese nanoparticles reduce free-radical load and improve oxygenation [139]. Based on these properties, MONPs provide a promising platform for developing metal nanoparticles as redox-active nanozymes to combat oxidative stress and inflammatory responses associated with SARS-CoV-2-related neurological pathologies.

Selenium and Nanoselenium
Selenium is a micronutrient that supports mammalian redox biology by maintaining normal intracellular ATP and Ca 2+ homeostasis [97]. Food sources of selenium include grains, nuts, vegetables, seafood, meat, and dairy products [140,141]. Numerous epidemiological studies have shown a link between low levels of selenium and an increased risk of developing various pathologies, including cancer, neurodegenerative disorders, cardiovascular problems, and infectious diseases. Most of the beneficial effects of selenium result from its incorporation as selenocysteine into selenoproteins, a vital class of proteins. Selenocysteine is the 21st proteinogenic amino acid encoded by a UGA codon, which is usually the signal for the termination of protein synthesis [141]. Therefore, selenoproteins play a crucial role in the antioxidant defense mechanisms that maintain redox homeostasis, together with CAT, SOD, GSH, vitamin E, GPx, thioredoxin reductase, carotenoids, and ascorbic acid [142,143]. Recently, selenium levels have been found to favorably connect with COVID-19 survivors compared with non-survivors [144]. This hypothesis was supported by the reported lower selenium levels in COVID-19 patients (69.2 ± 8.7 ng/mL) compared with the controls (79.1 ± 10.9 ng/mL) [144]. Of note, Moghaddam et al. have established a clear correlation between the mortality in patients with COVID-19, low selenium levels, and selenoprotein P (SELENOP) [145].
Because selenium may accumulate in tissues and have lethal effects at high dosages on healthy tissues, nanoscale selenium (selenium nanoparticles, SeNPs) may be a highly efficient formulation with enhanced antioxidant activity and lower toxicity for targeted delivery in various pathologies, especially in viral infections. Studies have revealed that SeNPs efficiently protected C2C12 cells from H 2 O 2 exposure by suppressing ROS and promoting myogenic differentiation. The latter is accompanied by an elevation of myogenic-related mRNA levels (MyoD, MyoG, and α-actinin), which promote multinucleated mature myoblasts and enhance the production of antiapoptotic proteins (e.g., BCL-2) [146]. Moreover, selenium nanoparticles stabilized with chitosan (Ch-SeNPs) have been reported to inhibit the Aβ 42 aggregation produced by some amino acid enantiomers [147]. In the Hepatitis B infection, the delivery of a SeNPs/HBsAg vaccine in vivo impacted lymphocyte proliferation, elevated IFNγ levels, and triggered a Th1 response [148]. Thus, SeNPs may be a highly efficient therapeutic strategy against SARS-CoV-2 by enhancing humoral immune responses [148].

Other Inorganic Antioxidant Nanomaterials and Carbon-Based Nanomaterials
Platinum-based nanomaterials have been fabricated as another class of NPs with fascinating outcomes as nano-antioxidants that are able to mimic enzymatic CAT and SOD activities. Takamiya et al. have utilized Pt nanoparticles as a preventative approach to lessen the effects of ischemic stroke and to repair damages, while maintaining the structure and neurological capabilities of the neurovascular unit (NVU) in a mouse model of cerebral infarction [149]. Mu et al. have developed a trimetallic (triM) nanozyme with a multienzyme-mimetic activity that functioned as an effective scavenger of ROS and RNS in brain traumatic injuries [150].
Furthermore, yttrium oxide nanoparticles (Y 2 O 3 ) have been reported as a neuroprotector in HT-22 mouse hippocampal neuronal cells in a rat model of lead-induced neuronal damage and an in vivo model of photo degeneration [151].
Several carbon-based nanomaterials, including fullerene, graphene nanosheets, carbon nanotubes, and carbon clusters, have been investigated as antioxidants and as possible treatments for some CNS disorders [152,153].
Two-dimensional carbon-based nanomaterials have also demonstrated antioxidant properties as indicated in the work of Qiu et al., who used electron paramagnetic resonance spectroscopy (EPR) to examine graphene's capability to scavenge ROS [154]. The authors found that graphene oxide was able to do so for both OH and O 2 radicals.
Altogether, these findings could lay the basis for the future exploration of both organicand inorganic-based nanodelivery systems in post-COVID-19 neurological diseases characterized by high levels of oxidative stress.

Nanodelivery of Antioxidant Enzymes
To combat oxidative and nitrosative stress, cells employ a defense system including the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) antioxidant enzymes. Regarding the nanosystems for the delivery of antioxidant enzymes, the ability of the combination of NPs and tissue plasminogen activator (t-PA + nano-SOD/CAT) to stimulate the migration of stem/progenitor cells from the subventricular zone and circulation, and thus to promote neurogenesis, has been recently emphasized [155]. The inhibition of edema formation has suggested the protection of the BBB from reperfusion injury in a thromboembolic rat stroke model [155]. Another study has reported a significant reduction in mitochondrial ROS activities, increased mitochondrial membrane potential, reduced calcium levels, and also higher adenosine triphosphate (ATP) content after the intravenous administration of nano-SOD/CAT, 6 h after injury in a rat severe contusion model of spinal-cord injury (SCI), thus protecting cell apoptosis and further degeneration [156].
A summary of the outcomes of antioxidant-based nanoparticles and nanoconjugates with the potential to improve the neurological consequences of COVID-19 is presented in Table 1.

Conclusions
Current evidence on the prevalence of post-COVID-19 symptoms and the neurological cost of COVID-19 is a wake-up call for effective treatments. Indeed, substantial documentation buttresses the hypothesis that oxidative stress plays a crucial role in disease progression. Using antioxidants to scavenge free radicals appears to be an approach towards the right direction. Although antioxidants have limitations, nanotechnology-based drug-delivery systems can serve as a tool to combat such drawbacks. Nanotechnology allows the combination of different antioxidant agents in nanoscale reservoirs to improve their delivery, efficacy, and bioavailability. Furthermore, several phytochemicals may have synergistic antiviral effects when co-administered, and thus show superior efficacy in improving the clinical outcomes of neurological long COVID. Considering that oxidative stress is a common pathophysiological process in multiple diseases, an effective antioxidant nanomedicine-based approach could have broad therapeutic applications in many clinical settings.