Abstract
Graphical abstract
Abstract
Reactive oxygen species (ROS) are important signaling molecules that play key roles in the progression of inflammatory disorders. Owing to a mismatch of the antioxidant level to balance the overproduction of ROS, the induced chronic inflammation can lead to several type of diseases such as cancer, inflammatory bowel disease, atherosclerosis, diabetes or neurodegenerative disorders. Over the last years, nanomedicine has shown tremendous promise in ROS-regulating approaches. The development of advanced redox-active nanomaterials opened the range of possibilities to anti-inflammatory therapies, with the production of ROS-responsive nanosystems enabling targeted drug delivery or with the manufacture of ROS-scavenging nanomaterials reducing ROS excess levels. This review summarizes the latest developments and novel designs of ROS-based nanomedicines and discusses their therapeutical strategies and applications.
Introduction
Reactive oxygen species (ROS) are free radicals derived from molecular oxygen naturally generated during cellular metabolic activities and produced in response to exogenous stressors (Pizzino et al. 2017). The most prominent feature of ROS is their high reactivity to interact and cause damages to cellular components like lipids, proteins and nucleic acids. Although they play an essential role in regulating various physiological biological functions, an excess ROS level leads to oxidative stress which is related to cellular damage and aging process, and is implicated in the development of various diseases such as neurodegenerative disorders, chronic diseases and cancers (Hayes et al. 2020, Sharifi-Rad et al. 2020, Merelli et al. 2021).
Under physiological conditions, ROS levels are regulated by antioxidants that inhibit the oxidation process at the root of the production of free radicals. This redox balance is subtlety ensured either by endogenous production and external supplementation issue from common diet. However, in pathological conditions related to ROS overproduction, antioxidant defense is overwhelmed by sustained inflammation resulting in a disturbed redox balance (Poljsak et al. 2013).
Significant advances in drug delivery nanotechnology fostered the improvement of antioxidant-based strategies to counteract ROS overproduction (Tao & He 2018, Yang et al. 2019, Huang et al. 2021). In this review different nanomedicine-based approaches aiming at restoring the redox balance under pathologic conditions are highlighted. First, the different types of ROS-scavenging nanomaterials to reduce oxidative stress and prevent cellular damages are discussed. Then, strategies focused on ROS-responsive nanomaterials to provide targeted and controlled drug delivery have been investigated.
Oxidative stress: exploring the interactions between ROS and antioxidants
Over the last years, a wealth of information has been accumulated on the fundamental importance of ROS for physiology as functional signaling entities. ROS are oxygen-containing molecules involved in numerous biochemical reactions (Parrish 2010). They are naturally produced either as a by-product of cellular metabolic processes such as cellular respiration and enzymatic reactions, or in response to environmental stressors like pollution and radiation (Dickinson & Chang 2011, Cortassa et al. 2014). The reduction of oxygen-containing molecules such as hydrogen peroxide or molecular oxygen leads to the formation of several ROS including superoxide, hydrogen peroxide, hydroxyl radical and hydroxyl ion. The presence of unpaired electrons in the outer electron shell of molecular oxygen makes ROS very reactive molecules to reduce reactions.
At normal levels, these molecules play a key role in cell survival by regulating cellular signaling pathways and processes or fighting viral infections (Schieber & Chandel 2014, Li et al. 2017). The pleiotropy of ROS in physiological signaling is linked by its involvement in the MAPK and AP-1 pathways, in which ROS are activators for the regulation of cell proliferation, differentiation and survival (Son et al. 2011, Mittler 2017). In other signaling processes such as nuclear factor kappa B (NF-kβ) or JAK/STAT pathways, ROS are activators leading to the regulation of cytokine signaling and of the expression of several genes involved in inflammation (Simon et al. 1998, Morgan & Liu 2011).
However, while ROS play important roles in cellular processes, their excessive production can also disrupt these signaling pathways and induce undue apoptosis, cell proliferation and inflammation. Furthermore, the high level of ROS can cause oxidative stress and lead to cellular damages through the oxidation of cellular components such as lipids, proteins and DNA (Halliwell et al. 2015). This oxidative damage can trigger cellular dysfunctions and has been implicated in the development of various diseases as neurodegenerative disorders and cancers. In fact, elevated levels of ROS and deregulated redox signaling can be used as a hallmark of cancer progression (Shah & Rogoff 2021). Causal connection between excessive ROS production and premature aging has been also widely studied. In addition to oxidative stress on cellular components, ROS-related mitochondria damages and inflammation have been demonstrated to elicit age-related pathologies or early cellular senescence (Hajam et al. 2022, Li et al. 2023). It is worth noting that ROS excess can suppress the function of immune cells, impairing their ability to respond to pathogens and thus contributing to chronic infections (Yang et al. 2013).
Overall, maintaining a basal level of ROS production is crucial to enable proper redox biology reactions and the regulation of numerous processes essential for life while an imbalance in favor of an excess of ROS fosters oxidative stress, cellular damage and diseases. To counteract excess levels of ROS, cells maintain a cellular redox homeostasis by an elaborate endogenous antioxidant defense system (Fig. 1).
Representative illustration of the cellular redox homeostasis balanced from antioxidant and ROS levels.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-23-0021
The first line of defense against oxidative stress arises from three main proteins with enzyme activity: superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). While SOD converts highly reactive superoxide radicals into hydrogen peroxide and molecular oxygen, CAT and GPx catalyze hydrogen peroxide into water, alcohol or molecular oxygen (Aguilar et al. 2016, Wang et al. 2018). The second line is based on nonenzymatic antioxidant molecules such as glutathione, alpha-lipoic acid, coenzyme Q, ferritin and uric acid, which are endogenously produced by cells and act to scavenge ROS, end chain reactions by free radicals and repair ROS-related damages (Mirończuk-Chodakowska et al. 2018).
Cellular redox homeostasis is also balanced with exogenous antioxidant issues from diet and in particular fruits and vegetables. Vitamin C and E, carotenoids (e.g. β-carotene, lutein, lycopene) and phenolics (e.g. flavonoids, hydroxybenzoic and phenolic acids, stilbene derivatives) are presented as the main exogenous antioxidants provided by food nutrients (Maleki et al. 2019). Some clinical studies demonstrated the benefits of a diet rich in antioxidants to prevent oxidative stress and various related diseases, as well as supporting the immune system (Willett 2006, Hawkins et al. 2022). Thus, many of these antioxidants have been studied as potential therapeutic strategies for a variety of diseases (Ngo et al. 2019, Mahjabeen et al. 2022). However, the efficiency of antioxidant molecules may be impeded by their physicochemical properties. Many antioxidants have restricted bioavailability, poor solubility in water and short half-time, resulting in low absorption and difficulty reaching the targeted tissues (Forman & Zhang 2021). Thereby, the use of nanomedicine appears to be a promising approach to overcome the limitations of conventional delivery approaches.
Nanomedicine-based strategies against ROS imbalance
From the first clinically approved nanomedicine for the encapsulation of doxorubicin (DOX) in 1995 to the recent booming success of nanoparticle (NP)-based mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), nanomedicines proved to increase therapeutic efficacy of treatments in a wide range of diseases (DOXIL approved by FDA 1995, Baden et al. 2020, Sahin et al. 2020). Drug-delivery vehicles represent a suitable strategy to provide safe and efficient delivery of therapeutic compounds (such as small chemical molecules, nucleic acids or peptides) and improve their bioavailability (Mitchell et al. 2021). The encapsulation or association to nanocarriers, aimed at solving solubility or instability issues by protecting the payload from the extracellular media, minimizing enzymatic or environmental degradation (Tenzer et al. 2013). Additionally, nanosystems can be engineered with specific functions for precise site targeting or controlled release of the payload (Blanco et al. 2015).
In this context, nanomedicine have led to gain an interest for the use of drug-delivery carriers to enhance the pharmacokinetic properties of antioxidants. Nevertheless, suitable concentrations in the targeted tissues remain also a main challenge to avoid poor inefficient activity or over exposure that can have an opposite effect and enhance oxidative stress (Podmore et al. 1998, Palozza 2009). Thus, the interest in the use of nanomedicine for ROS-related applications quickly evolved toward the development of alternative nanosystems-related strategies. The different ROS-based nanomaterials can be classified in two main categories. ROS-scavenging nanosystems mainly based on inorganic nanomaterials aim to trap ROS excess and reduce overall oxidative stress. On the other hand, ROS-responsive nanomaterials mainly focused on organic nanomaterials are designed to undergo specific changes in response to ROS excess levels, triggering targeted payload release. An overview of the different nanosystems and strategies described in the next paragraphs of the present review is given in Table 1.
Recapitulative table of the different ROS-based nanomedicine strategies toward anti-inflammatory therapies. Ce, cerium oxide; DMA, dimethylacrylamide; IBD, inflammatory bowel disease; MIP, molecularly imprinted polymer; PEG, polyethylene glycol; TNF-α, tumor necrosis factor alpha).
| Type of ROS-active nanomaterial/composition | Medical application | Properties | Reference |
|---|---|---|---|
| ROS-scavenging nanomedicine | |||
| Nanozymes | |||
| CeNPs-PEG | Neurodegenerative disorders | - Scavenge overproduced ROS after oxygen and glucose deprivation/reoxygenation treatment on resident brain murine microglia cell line | Zeng et al. (2018) |
| - Reshaping of pro-inflammatory M1-like microglia phenotype towards anti-inflammatory M2-like microglia phenotype | |||
| CeNPs-MIP | Atherosclerosis | - Alleviate lipid peroxidation-induced inflammatory response in macrophages | Wen et al. (2022) |
| - Inhibit atherosclerosis progression in atherosclerotic Apoe-/- mouse models | |||
| Mn3O4 NPs | Neurodegenerative disorders | - Able to mimic the SOD, CAT and GPx antioxidant activities | Singh et al. (2017) |
| Mn3O4 coated with PEG | IBDs | - Reduce oxidative stress on H2O2 pretreated RAW264.7 macrophages | Cheng et al. (2021) |
| - Reduce in vivo expression of pro-inflammatory cytokines TNF-α and interleukin 1β | |||
| Pt-NPs | IBDs | - Inhibit overproduction of ROS and interleukin 6 and TNF-α proinflammatory cytokines on murine RAW264.7 macrophage cell line | Zhu et al. (2019) |
| Pt@PCN222-Mn | IBDs | - Therapeutic efficacy toward colitis mice models | Liu et al. (2020) |
| Free-radical trapper | |||
| DMA-co-TEMPO | Acute local inflammation | - Local administration leads to decrease of ROS levels and TNF-α | DeJulius et al. (2021) |
| -Systemic administration reduces ROS levels | |||
| Fullerene C60 | Pulmonary inflammation | - Reduction of neutrophils and polarization of M1 and M2 macrophages in in vivo murine model | Lim et al. (2020) |
| Redox ROS scavenging | |||
| PEG2000-bilirubin NPs | Ulcerative colitis | - In vitro H2O2-scavenging properties | Lee et al. (2016), Keum et al. (2020) |
| - Reduction of acute inflammation in colitis murine model after intravenous administration | |||
| - Reduction of intracellular level of ROS and proinflammatory cytokines in psoriasis mice model after topical administration | |||
| CC-NPs (curcumin payload) | IBDs | - Reduction of TNF-α secretion and neutrophils infiltration in DSS-induced colitis mice model after local administration | Beloqui et al. (2014) |
| PF127-NPs (curcumin payload) | IBDs | - Reduction of pro-inflammatory cytokines and increase of anti-inflammatory cytokines in DSS-induced colitis mice model after oral administration | Chen et al. (2019) |
| ROS-responsive nanomedicine | |||
| ROS-induced solubility changes | |||
| Thioether-based NPs (melatonin payload) | Sepsis-induced acute liver injury | - Controlled release at the inflammation site in sepsis-induced acute liver murine model after oral administration | Chen et al. (2017) |
| - Reduction of oxidative stress, inflammation and liver injuries in sepsis-induced acute liver murine model after oral administration | |||
| Selenium-based NPs (doxorubicin payload) | Cancer | - Efficient and fast drug release in vitro in He-La cells | Liu et al. (2013) |
| - High therapeutic efficiency in vitro in He-La cells | |||
| Tellurium-based NPs | Inflammatory-related diseases | - Ultrasensitive to ROS level | Wang et al. (2022) |
| - Reversible redox-sensitive structure | |||
| ROS-induced cleavage | |||
| Thioketal-based NPs | IBDs | - Reduction of TNF-α colonic expression level in colitis-induced mice model after oral administration | Wilson et al. (2010) |
| Aryl boronic ester-based NPs | Inflammatory-related diseases | - High degradation capacity in presence of ROS | de Gracia Lux et al. (2012) |
| Inorganic-based NPs | Cancer | - High degradation capacity in tumor microenvironment | Choi et al. (2022) |
| - Faster clearance in vivo compared to conventional inorganic NPs reducing their in vivo accumulation |
ROS-scavenging nanomaterials against oxidative stress
Progress in nanotechnologies allowed the design of nanomaterials endowed with ROS-scavenging properties to ameliorate ROS-related inflammatory conditions (Li et al. 2020). ROS-scavenging NPs can be divided in three categories depending on their different mechanism of action: nanozymes, free-radical trapper NPs and redox ROS-scavenging NPs (as illustrated in Fig. 2) (Huang et al. 2021).
Representative classification of the different types of ROS-scavenging nanosystems.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-23-0021
Nanozymes
Nanozymes are nanomaterials exhibiting intrinsic enzyme-like characteristics that have been developed to overcome the limitations exhibited by natural enzymes. They are generally low-cost, recyclable, stable in a harsh environment, easy to mass-produce and easy to multifunctionalize (Liang & Yan 2019). Nanozymes are mainly made by metal and metal oxides because of the metallic active center ability to mimic the catalytic electronic redox process of natural enzymes such as CAT, SOD or GPx (Ren et al. 2022).
CeO2 NPs, defined as nanoceria or ceria NPs, exhibit strong antioxidant properties. They have SOD- and CAT-mimetic activities; thus, they are able to protect cells from the excessive presence of ROS (Nelson et al. 2016). Their ROS-scavenging capacity is due to the coexistence of Ce3+ and Ce4+ forms that establish the redox couple responsible for their catalytic activities. Nanoceria can scavenge ROS by the reversible binding of the oxygen on their surface (Ferreira et al. 2018). Zeng et al. developed ceria NPs coated with polyethylene glycol (CeNPs-PEG) to scavenge the ROS overproduced after oxygen and glucose deprivation/reoxygenation treatment on a resident brain murine microglia cell line. In addition, they observed that the antioxidant activity of these NPs leads to the reshaping of the pro-inflammatory M1-like microglia phenotype towards the anti-inflammatory M2-like-microglia phenotype showing a neuroprotective effect (Zeng et al. 2018). Aiming at combining CeNPs antioxidant and anti-inflammatory activities with a cholesterol-lowering effect, Wen et al. coated CeO2 NPs with a molecularly imprinted polymer (MIP) to reduce lipid levels in atherosclerosis. To obtain MIP, cholesterol is imprinted on the surface of CeO2 NPs by radical polymerization of functional monomers. This strategy is based on the use of artificial receptors MIP able to recognize and sequestrate cholesterol present in atherosclerotic plaques. CeO2@MIP presented an average diameter of 5 nm that exhibits SOD and CAT-like activity, thus being able to alleviate the lipid peroxidation-induced inflammatory response in macrophages and inhibit the atherosclerosis progression in atherosclerotic ApoE−/− mouse models (Wen et al. 2022).
Among the different elements selected to produce nanozymes, manganese (Mn) has attracted wide attention due to its low-cost, valence-rich transition, and excellent biocompatibility in several biomedical applications (Li & Yang 2018). Singh et al. have studied multienzyme-like activity of the Mn3O4 NPs demonstrating as these NPs were able to mimic the SOD, CAT and GPx antioxidant activities, scavenging different ROS species (Singh et al. 2017). Cheng et al. exploited Mn3O4 coated with PEG as a novel therapeutic approach for the treatment of inflammatory bowel disease (IBD). In vitro studies on RAW264.7 macrophages pretreated with H2O2 demonstrated the ROS-scavenging capacities of Mn3O4 NPs to reduce oxidative stress in a dose-dependent manner. Moreover, in vivo, the ROS-scavenging activity of these NPs has been demonstrated in dextran sulfate sodium (DSS)-induced colitis mice by reducing the expression of pro-inflammatory cytokines, TNF-α and interleukin 1β, that largely contribute to the progression of IBD (Cheng et al. 2021).
Platinum NPs (Pt-NPs) have also been reported to have SOD- and CAT-mimetic properties. Considering their ability to catalyze hydrogen peroxide in molecular oxygen, Pt-NPs are widely applied as antioxidant and anti-inflammatory agents. Zhu et al. demonstrated as Pt-NPs can directly inhibit the overproduction of ROS and proinflammatory cytokines such as interleukin 6 and TNF-α on murine RAW264.7 macrophage cell line, relieving the local and systemic inflammation in a colitis mice model (Zhu et al. 2019). Liu et al. developed a novel therapeutic strategy to treat IBD by synthetizing Pt-Mn nanozymes (named Pt@PCN222-Mn) with SOD/CAT mimetic cascade activity. These nanozymes exhibited higher therapeutic efficacy toward ulcerative colitis and Crohn disease mice models, when compared to mice treated with an unintegrated mixture of the two nanozymes (Liu et al. 2020).
Free-radical trapper
Free-radical trapper NPs have the particularity to capture unpaired electrons from free radicals. Different ROS-scavenging nanomaterials such as 2,2,6,6-tetramethylpiperidinenoxyl (TEMPO) and fullerene have been exploited for their potential of free-radical trapper in the treatment of different pathological conditions (Dellinger et al. 2013, Polaka et al. 2022).
TEMPO is a stable radical that can scavenge superoxide and peroxide by capturing their unpaired electrons. TEMPO antioxidant activity is due to its ability to easily donate the free electron present on the nitroxide to form the oxoammonium cation. The oxoammonium cation can then be reduced by •O2− back to the nitroxide radical. The nitroxide/oxoammonium redox couple is responsible of the antioxidant TEMPO activity (Soule et al. 2007). TEMPO is inexpensive and easy to produce, however, since it is a small molecule, it is limited by the fast clearance from the body. To increase its in vivo bioavailability, Dejulius et al. have developed a polymeric form of TEMPO [poly(TEMPO)] copolymerized with the hydrophilic monomer dimethylacrylamide (DMA) to enhance its water solubility. They found in vitro and in vivo that DMA-co-TEMPO copolymers possess higher ROS-scavenging and anti-inflammatory properties compared to the free TEMPO. The local administration of DMA-co-TEMPO copolymers in an air pouch model of acute local inflammation leads to the decrease of the ROS levels and TNF-α present in the pouch exudate. In addition, the systemic administration of TEMPO in a footpad model of inflammation also reduces ROS levels (DeJulius et al. 2021).
Fullerene C60 is a form of crystalline carbon that contain a conjugated double bond with a good electron affinity. It is an excellent electron acceptor with ROS-scavenging properties. Lim et al. exploited fullerene C60 antioxidant effect to resolve the pulmonary inflammation in an in vivo murine model. Fullerene C60 NPs have demonstrated their ROS-scavenging properties to induce different cellular and molecular events, such as the reduction of neutrophils and polarization of M1 and M2 macrophages that lead to the resolution of pulmonary acute inflammation (Lim et al. 2020).
Redox ROS-scavenging NPs
The last group of NPs used as antioxidant and anti-inflammatory agents are the redox ROS-scavenging NPs. They are based on the delivery of ROS-scavenging drugs (e.g. bilirubin or curcumin) using conventional nanomedicine, and are used to modulate the ROS levels in different pathological conditions (Karthikeyan et al. 2020, Adin 2021).
Bilirubin is an endogenous tetrapyrrole mainly derived from the breakdown of the hemoglobin in senescent erythrocytes and from the degradation of heme-containing proteins (Kalakonda et al. 2023). Its antioxidant properties are strictly related to its chemical structure: the hydrogen on the carbon bridge at the tenth position can directly scavenge the ROS and suppress the oxidative damage by binding the lone pair electron of the oxygen radicals (Stocker et al. 1987). Considering its powerful antioxidant and anti-inflammatory properties, bilirubin has been investigated to treat IBD and other inflammatory-related diseases, brain disorders, cardiovascular diseases, and ischemia-reperfusion injury (Kim & Park 2012, Chen et al. 2020). However, due to its high lipophilicity, bilirubin cannot be intravenously administered and as it is highly protein-bound in plasma, it is quickly metabolized and eliminated through liver and renal excretion. To improve its bioavailability, Lee et al. designed self-assembled PEG2000-bilirubin NPs (BRNPs) for the treatment of ulcerative colitis. BRNPs showed in vitro high H2O2-scavenging properties, protecting cells from hydrogen peroxide-induced cytotoxicity. Moreover, studies conducted on ulcerative colitis murine model, demonstrated that BRNPs preferentially accumulate on the site of inflammation after intravenous injection and significantly reduce the progression of acute inflammation in the colon of the mice (Lee et al. 2016). Keum et al. showed that the topical administration of BRNPs reduced the intracellular level of ROS and the expression of proinflammatory cytokines in the keratinocytes of a psoriasis animal model, ameliorating the psoriasis-like skin inflammation symptoms (Keum et al. 2020).
Curcumin is the yellow pigment derived from Curcuma longa Linn. This antioxidant and anti-inflammatory molecule has been proposed as treatment for several pharmaceutical applications, such as neurodegenerative diseases, cancer, IBD and ethanol-induced oxidative injuries in brain, liver, heart and kidney (Barzegar & Moosavi-Movahedi 2011, Jakubczyk et al. 2020, Karthikeyan et al. 2021). Curcumin activity is given by the hydroxyl and methoxy groups present on its structure and thanks to its ability to interact with the different antioxidant enzymes, such as CAT, SOD and GPx. Moreover, it has been proven that curcumin can negatively regulate proinflammatory interleukins (IL-1, IL-2, IL-6, IL-8 and IL-12) and cytokines such as TNF-α (Kocaadam & Şanlier 2017). However, curcumin is characterized by poor water solubility and low bioavailability, hampering its application as it is. Beloqui et al. encapsulated curcumin in pH-sensitive polymeric NPs (CC-NPs) made by poly(lactic-co-glycolide) acid (PLGA) and a polymethacrylate polymer. In vivo studies in DSS-induced colitis mice model showed the reduction of TNF-α secretion and neutrophils infiltration after local delivery of CC-NPs, while maintaining the colon structure similar to healthy mice (Beloqui et al. 2014). To improve the accumulation of curcumin in colitis tissues, Chen et al. loaded curcumin into porous PLGA NPs functionalized with pluronic F127 (named PF127-NPs) (Chen et al. 2019). Oral administration of PF127-NPs in DSS-induced colitis mice reduced the expression of pro-inflammatory cytokines while increasing the production of anti-inflammatory ones. Moreover, less injury areas in the mucosa have been found on mice treated with porous PF127-NPs and the intestinal cellular morphology was similar to that found in the healthy mice.
ROS-related microenvironment: an opportunistic route for ROS-responsive nanosystems
Compared to conventional nanocarriers ROS-responsive nanosystems have elicited widespread popularity in biomedical research for their interesting properties in controlling payload release in targeted cells or tissues that overproduce ROS. There are two main drug release mechanisms in the area of ROS-responsive nanomedicine, depending on the selection of the biomaterials. The mechanisms of drug release can be ascribed to solubility changes or cleavage of the polymer in ROS microenvironment that led to the disassembly of the entire nanosystems (Fig. 3).
Common ROS-responsive linkers used in the design of ROS-responsive nanomedicine.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-23-0021
ROS-induced solubility change
ROS-responsive nanocarriers can be designed using a sensitive-polymer containing chemical functions that undergo hydrophobic–hydrophilic transition in contact with ROS. Thus, in an oxidized microenvironment, the three-dimensional nanocarrier conformation changes, leading to the overall carrier structure disassembly and the release of the drug.
Thioether-functionalized polymers are part of the most studied components in ROS-sensitive compounds area (Xu et al. 2016). Thioether are hydrophobic sulfide functions that are converted into hydrophilic sulfoxide and sulfone functions in contact with ROS (Criado-Gonzalez & Mecerreyes 2022). Chen et al. designed self-assembly nanocarriers made of polyethylene glycol (PEG) and poly(propylene) sulfide (PPS) blocks for the delivery of the antioxidant melatonin, to treat inflammation related to sepsis-induced acute liver injury (Chen et al. 2017). Sulfide functions in PPS motif enable a fast nanocarrier dissolution in the presence of ROS. In vivo biodistribution studies in a murine model of sepsis-induced acute liver injury, revealed that oral administration of PEG-PPS-melatonin nanocarriers allowed a controlled and efficient drug release in the inflamed site, and significantly reduced oxidative stress, inflammation and liver injuries.
Other interesting ROS-sensitive biomaterials are Se-containing polymers as Se functions are oxidized into hydrophilic selenoxide and selenone functions in oxidative conditions (Xu et al. 2016). Liu et al. designed micelles loaded with DOX for cancer treatment, made of a hyperbranched polymer based on an alternation of hydrophobic selenide groups and hydrophilic phosphate units (Liu et al. 2013). ROS responsiveness was investigated in human cervical carcinoma (He-La) cells. Confocal studies revealed a fast release and DOX accumulation in cell nuclei treated with ROS-responsive micelles compared to nonresponsive micelles. Furthermore, ROS-responsive micelles were able to reduce He-La cell viability, highlighting their ability to disassemble in an ROS microenvironment and trigger DOX release.
Tellurium (Te)-based biomaterials have been proposed as ROS-ultrasensitive polymers. Interestingly, they are more sensitive to low ROS concentrations compared to thioether- and Se- based polymers previously mentioned (Cao et al. 2015). In fact, telluride linkage has similar chemical properties to sulfide and selenium bonds but has a lower electronegativity. Te-based biomaterials are of interest for the treatment of cancer cells with a low ROS level microenvironment (10–100 µM H2O2 concentration) where conventional ROS-sensitive polymers can have marginal benefice. Wang et al. designed an ultrasensitive ROS-responsive nanosystem made by the coassembly of a phospholipid and a Te-based polymer. Interestingly, the structure also exhibits reversible redox properties (Wang et al. 2022). As proof-of-concept, electrospray ionization mass spectrometry (ESI-MS) analysis confirmed that the developed nanosystem was ROS-sensitive at very low ROS level. Following 1 h incubation with 100 µM H2O2, Te switched from reduced to oxidized state on coassemblies. Moreover, 1H NMR spectra showed that the typical peaks of oxidized Te atoms disappeared after reduction reaction, confirming that the structure remained the same after oxidation. Given their properties, this delivery system represents a promising approach to reduce the increased oxidative stress in inflammatory-related diseases.
ROS-induced cleavage
Another ROS-responsive strategy relies on the development of materials containing ROS-sensitive linkages that can be selectively cleaved in response to ROS. There are different ROS-sensitive linkages, such as thioketal, disulfide and aryl boronic ester functions.
Thioketal functions are well-known ROS-sensitive bonds widely employed for providing functionalized polymers that cleave into ROS-conditions. Wilson et al. developed NPs based on poly-(1,4-phenylene acetone dimethylene thioketal) (PPADT) for the delivery of siRNA aiming to reduce the overexpression of TNF-α in the treatment of IBDs (Wilson et al. 2010). The ability of PPADT-based NPs to deliver siRNA locally in inflamed intestinal tissues was investigated in vivo in colitis-induced mice. Oral administration of siRNA-loaded PPADT nanosystems revealed a significant decrease in the TNF-α colonic expression level in comparison to siRNA delivered with β-glucan NPs used as nonresponsive nanosystems.
Aryl boronic ester is another ROS-sensitive chemical structure that undergoes degradation at low ROS concentrations. De Garcia et al. investigated aryl boronic ester functions to design new biocompatible ROS-responsive nanocapsules (NCs) able to undergo degradation at low concentrations of H2O2 (de Gracia Lux et al. 2012). Transmission electron microscopy (TEM) imaging showed that aryl boronic ester-based polymeric NPs exhibited a ripped and crumpled morphology compared to NPs not exposed to H2O2, confirming the morphological degradation in presence of ROS concentrations. In vitro release assay on activated neutrophils was designed to demonstrate the enhanced degradation capacity of aryl boronic ester-based polymeric NCs when in contact with ROS. Compared to control NPs formulated without aryl boronic ester functions, aryl boronic ester-based NCs presented an increased release of the fluorescent probe associated with the system.
Other than organic linkers, Choi et al. recently set up a promising hierarchical metallic suprananostructure made of branches composed of randomly interconnected primary gold nanocrystals, with small silver nanolinkers, as potential NPs for targeted drug delivery (Choi et al. 2022). The overall nanostructure showed a significant ROS-responsive capacity in the deregulated redox homeostasis microenvironment of tumor cells. Indeed, TEM micrographs of macrophage sections incubated with NPs revealed a dissociated morphology of particles in the intracellular compartment exhibiting a high level of ROS. Also, researchers demonstrated in vivo the ROS-responsive degradability of NPs in a mouse tumor model after intratumoral injection. Moreover, intravenous injection of NPs showed a faster clearance of these inorganic NPs compared to conventional gold NPs, limiting their in vivo accumulation and related-toxicity.
Conclusion and perspectives
In summary, maintaining a cellular redox homeostasis is essential to protect from oxidative stress and to prevent the onset of several diseases. The implication of oxidative stress in global health issues is from main concern for the future, with an aging global population and increased global pollution. In this perspective, developing ROS-based nanomedicine has been significantly investigated as a promising strategy to balance overproduction of ROS. As outlined in this review, the emergence of redox-active nanomaterials fostered the development of different types of ROS-based nanomedicine to provide advanced ROS regulating approaches by scavenging ROS excess or exploiting ROS microenvironment as an opportunistic route for drug delivery. Future perspectives aimed also to combine ROS-responsive biomaterials with other stimuli-responsive functions (e.g. pH, temperature or light sensitive) in order to provide combined multiresponsiveness properties and thereby more efficient nanocarriers.
Beyond the strategies described in this review, some additional directions can be considered to provide safe and efficient redox-based nanosystems. For instance, a precise dosage of nanosystems is a crucial issue that requires careful consideration to provide efficient ROS inhibition according to the pathological application while not exhibiting toxicity. The relevance of in vitro and in vivo models is a key point to mimic cellular and physiological inflamed environments and provide crucial insights on the therapeutic efficacy of the nanosystems. Furthermore, for clinical translation additional studies on long-term administration should be investigated to study biocompatibility and biodegradability of these approaches. Also, although the development of advanced redox-active nanomaterials allowed for efficient ROS regulation, large-scale pharmaceutical production of such sophisticated biomaterials remains limited, and subsequent studies to simplified biomaterial synthesis for an easier, scalable production are needed.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
MR: conceptualization, writing – original draft; HG: writing – original draft; GC: writing – original draft; GL: supervision, writing – review and editing.
References
Adin CA 2021 Bilirubin as a therapeutic molecule: challenges and opportunities. Antioxidants 10 1536. (https://doi.org/10.3390/antiox10101536)
Aguilar TAF, Hernández Navarro BC & & Pérez JAM 2016 Endogenous Antioxidants: A Review of Their Role in Oxidative Stress, A Master Regulator of Oxidative Stress - the Transcription Factor: IntechOpen, p. Nrf2. (https://doi.org/10.5772/65715)
Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CS, et al.2021 Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. New England Journal of Medicine384 403–416. (https://doi.org/10.1056/NEJMoa2035389)
Barzegar A & & Moosavi-Movahedi AA 2011 Intracellular ROS protection efficiency and free radical-scavenging activity of curcumin. PLoS One 6 e26012. (https://doi.org/10.1371/journal.pone.0026012)
Beloqui A, Coco R, Memvanga PB, Ucakar B, des Rieux A & & Préat V 2014 pH-sensitive nanoparticles for colonic delivery of curcumin in inflammatory bowel disease. International Journal of Pharmaceutics 473 203–212. (https://doi.org/10.1016/j.ijpharm.2014.07.009)
Blanco E, Shen H & & Ferrari M 2015 Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nature Biotechnology 33 941–951. (https://doi.org/10.1038/nbt.3330)
Cao W, Gu Y, Li T & & Xu H 2015 Ultra-sensitive ROS-responsive tellurium-containing polymers. Chemical Communications 51 7069–7071. (https://doi.org/10.1039/c5cc01779c)
Chen G, Deng H, Song X, Lu M, Zhao L, Xia S, You G, Zhao J, Zhang Y, Dong A, et al.2017 Reactive oxygen species-responsive polymeric nanoparticles for alleviating sepsis-induced acute liver injury in mice. Biomaterials 144 30–41. (https://doi.org/10.1016/j.biomaterials.2017.08.008)
Chen Q, Gou S, Ma P, Song H, Zhou X, Huang Y, Kwon Han M, Wan Y, Kang Y & & Xiao B 2019 Oral administration of colitis tissue-accumulating porous nanoparticles for ulcerative colitis therapy. International Journal of Pharmaceutics 557 135–144. (https://doi.org/10.1016/j.ijpharm.2018.12.046)
Chen Z, Vong CT, Gao C, Chen S, Wu X, Wang S & & Wang Y 2020 Bilirubin nanomedicines for the treatment of reactive oxygen species (ROS)-mediated diseases. Molecular Pharmaceutics 17 2260–2274. (https://doi.org/10.1021/acs.molpharmaceut.0c00337)
Cheng Y, Cheng C, Yao J, Yu Y, Liu Y, Zhang H, Miao L & & Wei H 2021 Mn3O4 nanozyme for inflammatory bowel disease therapy. Advanced Therapeutics 4 2100081. (https://doi.org/10.1002/adtp.202100081)
Choi H, Choi B, Han JH, Shin HE, Park W & & Kim DH 2022 Reactive oxygen species responsive cleavable hierarchical metallic supra-nanostructure. Small 18 e2202694. (https://doi.org/10.1002/smll.202202694)
Cortassa S, O’Rourke B & & Aon MA 2014 Redox-optimized ROS balance and the relationship between mitochondrial respiration and ROS. Biochimica et Biophysica Acta 1837 287–295. (https://doi.org/10.1016/j.bbabio.2013.11.007)
Criado-Gonzalez M & & Mecerreyes D 2022 Thioether-based ROS responsive polymers for biomedical applications. Journal of Materials Chemistry. B 10 7206–7221. (https://doi.org/10.1039/d2tb00615d)
de Gracia Lux C, Joshi-Barr S, Nguyen T, Mahmoud E, Schopf E, Fomina N & & Almutairi A 2012 Biocompatible polymeric nanoparticles degrade and release cargo in response to biologically relevant levels of hydrogen peroxide. Journal of the American Chemical Society 134 15758–15764. (https://doi.org/10.1021/ja303372u)
DeJulius CR, Dollinger BR, Kavanaugh TE, Dailing E, Yu F, Gulati S, Miskalis A, Zhang C, Uddin J, Dikalov S, et al.2021 Optimizing an antioxidant TEMPO copolymer for reactive oxygen species scavenging and anti-inflammatory effects in vivo. Bioconjugate Chemistry 32 928–941. (https://doi.org/10.1021/acs.bioconjchem.1c00081)
Dellinger A, Zhou Z, Connor J, Madhankumar AB, Pamujula S, Sayes CM & & Kepley CL 2013 Application of fullerenes in nanomedicine: an update. Nanomedicine (Lond) 8 1191–1208. (https://doi.org/10.2217/nnm.13.99)
DOXIL approved by FDA 1995. AIDS Patient Care 9 306. (https://doi.org/10.1089/apc.1995.9.306)
Dickinson BC & & Chang CJ 2011 Chemistry and biology of reactive oxygen species in signaling or stress responses. Nature Chemical Biology 7 504–511. (https://doi.org/10.1038/nchembio.607)
Ferreira CA, Ni D, Rosenkrans ZT & & Cai W 2018 Scavenging of reactive oxygen and nitrogen species with nanomaterials. Nano Research 11 4955–4984. (https://doi.org/10.1007/s12274-018-2092-y)
Forman HJ & & Zhang H 2021 Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nature Reviews. Drug Discovery 20 689–709. (https://doi.org/10.1038/s41573-021-00233-1)
Hajam YA, Rani R, Ganie SY, Sheikh TA, Javaid D, Qadri SS, Pramodh S, Alsulimani A, Alkhanani MF, Harakeh S, et al.2022 Oxidative stress in human pathology and aging: molecular mechanisms and perspectives. Cells 11 552. (https://doi.org/10.3390/cells11030552)
Halliwell B, Gutteridge JMC, Halliwell B & & Gutteridge JMC 2015 Free Radicals in Biology and Medicine, 5 th ed. Oxford: Oxford University Press. (https://doi.org/10.1093/acprof:oso/9780198717478.001.0001)
Hawkins J, Hires C, Dunne E & & Keenan L 2022 Effects of antioxidant supplement on immune health and physical wellbeing: a randomized, controlled trial. Advances in Integrative Medicine 9 180–184. (https://doi.org/10.1016/j.aimed.2022.06.007)
Hayes JD, Dinkova-Kostova AT & & Tew KD 2020 Oxidative stress in cancer. Cancer Cell 38 167–197. (https://doi.org/10.1016/j.ccell.2020.06.001)
Huang X, He D, Pan Z, Luo G & & Deng J 2021 Reactive-oxygen-species-scavenging nanomaterials for resolving inflammation. Materials Today. Bio 11 100124. (https://doi.org/10.1016/j.mtbio.2021.100124)
Jakubczyk K, Drużga A, Katarzyna J & & Skonieczna-Żydecka K 2020 Antioxidant potential of curcumin-A meta-analysis of randomized clinical trials. Antioxidants 9 1092. (https://doi.org/10.3390/antiox9111092)
Kalakonda A, Jenkins BA & & John S 2023 Physiology, bilirubin. In StatPearls. Treasure Island , FL: StatPearls Publishing.
Karthikeyan A, Senthil N & & Min T 2020 Nanocurcumin: a promising candidate for therapeutic applications. Frontiers in Pharmacology 11 487. (https://doi.org/10.3389/fphar.2020.00487)
Karthikeyan A, Young KN, Moniruzzaman M, Beyene AM, Do K, Kalaiselvi S & & Min T 2021 Curcumin and its modified formulations on inflammatory bowel disease (IBD): the story so far and future outlook. Pharmaceutics 13 484. (https://doi.org/10.3390/pharmaceutics13040484)
Keum H, Kim TW, Kim Y, Seo C, Son Y, Kim J, Kim D, Jung W, Whang CH & & Jon S 2020 Bilirubin nanomedicine alleviates psoriatic skin inflammation by reducing oxidative stress and suppressing pathogenic signaling. Journal of Controlled Release 325 359–369. (https://doi.org/10.1016/j.jconrel.2020.07.015)
Kim SY & & Park SC 2012 Physiological antioxidative network of the bilirubin system in aging and age-related diseases. Frontiers in Pharmacology 3 45. (https://doi.org/10.3389/fphar.2012.00045)
Kocaadam B & & Şanlier N 2017 Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Critical Reviews in Food Science and Nutrition 57 2889–2895. (https://doi.org/10.1080/10408398.2015.1077195)
Lee Y, Kim H, Kang S, Lee J, Park J & & Jon S 2016 Bilirubin nanoparticles as a nanomedicine for anti-inflammation therapy. Angewandte Chemie 55 7460–7463. (https://doi.org/10.1002/anie.201602525)
Li Z, Xu X, Leng X, He M, Wang J, Cheng S & & Wu H 2017 Roles of reactive oxygen species in cell signaling pathways and immune responses to viral infections. Archives of Virology 162 603–610. (https://doi.org/10.1007/s00705-016-3130-2)
Li L & & Yang X 2018 The essential element manganese, oxidative stress, and metabolic diseases: links and interactions. Oxidative Medicine and Cellular Longevity 2018 7580707. (https://doi.org/10.1155/2018/7580707)
Li CW, Li LL, Chen S, Zhang JX & & Lu WL 2020 Antioxidant nanotherapies for the treatment of inflammatory diseases. Frontiers in Bioengineering and Biotechnology 8 200. (https://doi.org/10.3389/fbioe.2020.00200)
Li X, Li C, Zhang W, Wang Y, Qian P & & Huang H 2023 Inflammation and aging: signaling pathways and intervention therapies. Signal Transduction and Targeted Therapy 8 239. (https://doi.org/10.1038/s41392-023-01502-8)
Liang M & & Yan X 2019 Nanozymes: from new concepts, mechanisms, and standards to applications. Accounts of Chemical Research 52 2190–2200. (https://doi.org/10.1021/acs.accounts.9b00140)
Lim CS, Porter DW, Orandle MS, Green BJ, Barnes MA, Croston TL, Wolfarth MG, Battelli LA, Andrew ME, Beezhold DH, et al.2020 Resolution of pulmonary inflammation induced by carbon nanotubes and fullerenes in mice: role of macrophage polarization. Frontiers in Immunology 11 1186. (https://doi.org/10.3389/fimmu.2020.01186)
Liu J, Pang Y, Zhu Z, Wang D, Li C, Huang W, Zhu X & & Yan D 2013 Therapeutic nanocarriers with hydrogen peroxide-triggered drug release for cancer treatment. Biomacromolecules 14 1627–1636. (https://doi.org/10.1021/bm4002574)
Liu Y, Cheng Y, Zhang H, Zhou M, Yu Y, Lin S, Jiang B, Zhao X, Miao L, Wei CW, et al.2020 Integrated cascade nanozyme catalyzes in vivo ROS scavenging for anti-inflammatory therapy. Science Advances 6 eabb2695. (https://doi.org/10.1126/sciadv.abb2695)
Mahjabeen W, Khan DA & & Mirza SA 2022 Role of resveratrol supplementation in regulation of glucose hemostasis, inflammation and oxidative stress in patients with diabetes mellitus type 2: a randomized, placebo-controlled trial. Complementary Therapies in Medicine 66 102819. (https://doi.org/10.1016/j.ctim.2022.102819)
Maleki SJ, Crespo JF & & Cabanillas B 2019 Anti-inflammatory effects of flavonoids. Food Chemistry 299 125124. (https://doi.org/10.1016/j.foodchem.2019.125124)
Merelli A, Repetto M, Lazarowski A & & Auzmendi J 2021 Hypoxia, oxidative stress, and inflammation: three faces of neurodegenerative diseases. Journal of Alzheimer’s Disease 82 S109–S126. (https://doi.org/10.3233/JAD-201074)
Mirończuk-Chodakowska I, Witkowska AM & & Zujko ME 2018 Endogenous non-enzymatic antioxidants in the human body. Advances in Medical Sciences 63 68–78. (https://doi.org/10.1016/j.advms.2017.05.005)
Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA & & Langer R 2021 Engineering precision nanoparticles for drug delivery. Nature Reviews. Drug Discovery 20 101–124. (https://doi.org/10.1038/s41573-020-0090-8)
Mittler R 2017 ROS Are Good. Trends in Plant Science 22 11–19. (https://doi.org/10.1016/j.tplants.2016.08.002)
Morgan MJ & & Liu ZG 2011 Crosstalk of reactive oxygen species and NF-κB signaling. Cell Research 21 103–115. (https://doi.org/10.1038/cr.2010.178)
Nelson BC, Johnson ME, Walker ML, Riley KR & & Sims CM 2016 Antioxidant cerium oxide nanoparticles in biology and medicine. Antioxidants 5 15. (https://doi.org/10.3390/antiox5020015)
Ngo B, Van Riper JM, Cantley LC & & Yun J 2019 Targeting cancer vulnerabilities with high-dose vitamin C. Nature Reviews. Cancer 19 271–282. (https://doi.org/10.1038/s41568-019-0135-7)
Palozza P 2009 Prooxidant actions of carotenoids in biologic systems. Nutrition Reviews 56 257–265. (https://doi.org/10.1111/j.1753-4887.1998.tb01762.x)
Parrish AR 2010. 2.27 Hypoxia/ischemia signaling. In Comprehensive Toxicology, 2 nd ed. McQueen CA Ed. Oxford: Elsevier, pp. 529–542. (https://doi.org/10.1016/B978-0-08-046884-6.00228-1)
Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, Squadrito F, Altavilla D & & Bitto A 2017 Oxidative stress: harms and benefits for human health. Oxidative Medicine and Cellular Longevity 2017 8416763. (https://doi.org/10.1155/2017/8416763)
Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry P & & Lunec J 1998 Vitamin C exhibits pro-oxidant properties. Nature 392 559–559. (https://doi.org/10.1038/33308)
Polaka S, Katare P, Pawar B, Vasdev N, Gupta T, Rajpoot K, Sengupta P & & Tekade RK 2022 Emerging ROS-modulating technologies for augmentation of the wound healing process. ACS Omega 7 30657–30672. (https://doi.org/10.1021/acsomega.2c02675)
Poljsak B, Šuput D & & Milisav I 2013 Achieving the balance between ROS and antioxidants: when to use the synthetic antioxidants. Oxidative Medicine and Cellular Longevity 2013 956792. (https://doi.org/10.1155/2013/956792)
Ren X, Chen D, Wang Y, Li H, Zhang Y, Chen H, Li X & & Huo M 2022 Nanozymes-recent development and biomedical applications. Journal of Nanobiotechnology 20 92. (https://doi.org/10.1186/s12951-022-01295-y)
Sahin U, Muik A, Derhovanessian E, Vogler I, Kranz LM, Vormehr M, Baum A, Pascal K, Quandt J, Maurus D, et al.2020 COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature 586 594–599. (https://doi.org/10.1038/s41586-020-2814-7)
Schieber M & & Chandel NS 2014 ROS Function in redox signaling and oxidative stress. Current Biology 24 R453–R462. (https://doi.org/10.1016/j.cub.2014.03.034)
Shah MA & & Rogoff HA 2021 Implications of reactive oxygen species on cancer formation and its treatment. Seminars in Oncology 48 238–245. (https://doi.org/10.1053/j.seminoncol.2021.05.002)
Sharifi-Rad M, Anil Kumar NV, Zucca P, Varoni EM, Dini L, Panzarini E, Rajkovic J, Tsouh Fokou PV, Azzini E, Peluso I, et al.2020 Lifestyle, oxidative stress, and antioxidants: back and forth in the pathophysiology of chronic diseases. Frontiers in Physiology 11 694. (https://doi.org/10.3389/fphys.2020.00694)
Simon AR, Rai U, Fanburg BL & & Cochran BH 1998 Activation of the JAK-STAT pathway by reactive oxygen species. American Journal of Physiology 275 C1640–C1652. (https://doi.org/10.1152/ajpcell.1998.275.6.C1640)
Singh N, Savanur MA, Srivastava S, D’Silva P & & Mugesh G 2017 A redox modulatory Mn3 O4 nanozyme with multi-enzyme activity provides efficient cytoprotection to human cells in a Parkinson’s disease model. Angewandte Chemie 56 14267–14271. (https://doi.org/10.1002/anie.201708573)
Son Y, Cheong YK, Kim NH, Chung HT, Kang DG & & Pae HO 2011 Mitogen-activated protein kinases and reactive oxygen species: how can ROS Activate MAPK pathways? Journal of Signal Transduction 2011 792639. (https://doi.org/10.1155/2011/792639)
Soule BP, Hyodo F, Matsumoto K-I, Simone NL, Cook JA, Krishna MC & & Mitchell JB 2007 The chemistry and biology of nitroxide compounds. Free Radical Biology and Medicine 42 1632–1650. (https://doi.org/10.1016/j.freeradbiomed.2007.02.030)
Stocker R, Yamamoto Y, McDonagh AF, Glazer AN & & Ames BN 1987 Bilirubin is an antioxidant of possible physiological importance. Science 235 1043–1046. (https://doi.org/10.1126/science.3029864)
Tao W & & He Z 2018 ROS-responsive drug delivery systems for biomedical applications. Asian Journal of Pharmaceutical Sciences 13 101–112. (https://doi.org/10.1016/j.ajps.2017.11.002)
Tenzer S, Docter D, Kuharev J, Musyanovych A, Fetz V, Hecht R, Schlenk F, Fischer D, Kiouptsi K, Reinhardt C, et al.2013 Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. Nature Nanotechnology 8 772–781. (https://doi.org/10.1038/nnano.2013.181)
Wang Y, Branicky R, Noë A & & Hekimi S 2018 Superoxide dismutases: dual roles in controlling ROS damage and regulating ROS signaling. Journal of Cell Biology 217 1915–1928. (https://doi.org/10.1083/jcb.201708007)
Wang G, Huang P, Wang L, Chen X, Zhou Y, Huang W & & Yan D 2022 ROS-responsive thioether-containing hyperbranched polymer micelles for light-triggered drug release. SmartMat 3 522–531. (https://doi.org/10.1002/smm2.1092)
Wen Y, Chen L, Zhou L, Leng F, Yang Z & & Yu C 2022 Bionic receptor for atherosclerosis therapy: molecularly imprinted polymers mediate unique cholesterol efflux and inhibit inflammation. Chemical Engineering Journal 430 132870. (https://doi.org/10.1016/j.cej.2021.132870)
Willett WC 2006 The Mediterranean diet: science and practice. Public Health Nutrition 9 105–110. (https://doi.org/10.1079/PHN2005931)
Wilson DS, Dalmasso G, Wang L, Sitaraman SV, Merlin D & & Murthy N 2010 Orally delivered thioketal nanoparticles loaded with TNF-α-siRNA target inflammation and inhibit gene expression in the intestines. Nature Materials 9 923–928. (https://doi.org/10.1038/nmat2859)
Xu Q, He C, Xiao C & & Chen X 2016 Reactive oxygen species (ROS) responsive polymers for biomedical applications. Macromolecular Bioscience 16 635–646. (https://doi.org/10.1002/mabi.201500440)
Yang B, Chen Y & & Shi J 2019 Reactive oxygen species (ROS)-based nanomedicine. Chemical Reviews 119 4881–4985. (https://doi.org/10.1021/acs.chemrev.8b00626)
Yang Y, Bazhin AV, Werner J & & Karakhanova S 2013 Reactive oxygen species in the immune system. International Reviews of Immunology 32 249–270. (https://doi.org/10.3109/08830185.2012.755176)
Zeng F, Wu Y, Li X, Ge X, Guo Q, Lou X, Cao Z, Hu B, Long NJ, Mao Y, et al.2018 Custom-made ceria nanoparticles show a neuroprotective effect by modulating phenotypic polarization of the microglia. Angewandte Chemie 57 5808–5812. (https://doi.org/10.1002/anie.201802309)
Zhu S, Zeng M, Feng G & & Wu H 2019 Platinum nanoparticles as A therapeutic agent against dextran sodium sulfate-induced colitis in mice. International Journal of Nanomedicine 14 8361–8378. (https://doi.org/10.2147/IJN.S210655)
