Since the first report of fullerene as an antioxidant, various fullerenes has been well investigated for its unique cage structure and scavenging activities towards OH and O₂ ^·-. The conjugated double bonds and the low-lying lowest unoccupied molecular orbital can account for their excellent antioxidative ability. Though they bears the name of “Radical Sponge,” their practical biomedical usages are often limited by the hydrophobic nature of original fullerenes. Derivatives including fullerenols, carboxyl-modified fullerenes, metal-modified fullerenes, and ethylenediamine-modified fullerenes usually exhibit better water solubility. Recent studies indicate that fullerenols can well eliminate free radicals both in vivo and in vitro. Better biocompatibility of fullerenol than native fullerene can be explained by its excretion in urine. So the fullerenol can be used to protect tissues or organs against oxidative injury induced by doxorubicin, Co. γ-rays and reduplicative chemotherapy (Figure 1A) (Zhou et al., 2017). The cage size, in particular, will affect the radical scavenging capability indicated by C₇₀ fullerenols’ superior protection over C₆₀-fullerenols. The reason for the difference can be attributed to the fact that C₇₀-fullerenols hold more intrinsically coupled double bonds, is closer to electrons, and is more polarizable.

Carboxyl modification is another strategy for hydrophilic alternation. As a high-performance neuroprotective antioxidant, C₆₀(C(COOH)₂)₃ has been shown to effectively prevent dopaminergic neuron apoptosis in vitro and protect cerebellar granule cells from apoptosis. Then, C₆₀(C(COOH)₂)₂ dots with similar structure were well synthesized and tested for their ability to protect the blood-brain barrier. As expected, C₆₀(C(COOH)₂)₂ dots can enter oxidized cerebral microvessel endothelial cells (CMECs) rather than normal cells and maintain CMEC integrity by inhibiting H₂O₂-induced F-actin depolymerization. It is of interest that carboxyl and cage size have an influence on the level of oxidative stress relaxation. To answer this question, different origins of acid including dimalonic acid, trimalonic acid, and quadrimalonic acid are selected and used to react with C₆₀ and C₇₀, respectively. These results suggest dimalonic acid-modified C₇₀ fullerenes and trimalonic acid-modified C₇₀ fullerenes exhibit an obviously more protective effect than others. The authors consider that the extended system and lower symmetric structure of the C₇₀ fullerene cage, which possess higher activated electron-deficient areas on the cage surface, can extremely quench various free radicals (Liu et al., 2013).

The typical representative of the metallofullerene family is Gd@C₈₂, while gadolinium endohedral metallofullerenol comprises a functionalized C₈₂ fullerene cage with metal trapped inside (Yin et al., 2009). It has been reported that the chemical and physical properties of gadolinium endohedral metallofullerenols are determined by the number and position of the hydroxyl groups on the fullerene cage. These metallofullerenols hold excellent scavenging activity against reactive oxygen species and exhibit great cell protection effect. Amino acid modification is also used to change the hydrophilic properties; Zhou et al. find that L-lysine modified C₇₀ fullerenes reveal higher scavenging activity than L-alanine modified C₇₀ fullerene (Zhou et al., 2018). The difference is because of the different integrity of fullerene cage. Recently, C₆₀-PDA-GSH are rationally designed and synthesized, and their relative cytoprotective effects against oxidative stress provide a candidate for the treatment of ROS-related diseases (Zhang et al., 2019). During the typical synthesis, C₆₀ is modified by the self-polymerization of dopamine into C₆₀-PDA hybrids. Subsequently, glutathione (GSH) is covalently immobilized onto the surface of C₆₀-PDA hybrids via Michael addition reaction. Inspired by above successful preparation of various derivatives and relative modifications, Chen and her colleagues compare the discrepancy of three fullerene derivatives on free radical scavenging efficiency (Yin et al., 2009). C₆₀[C(COOH)₂]₂ are found to be significantly less active than carboxyl-free fullerenes C₆₀(OH)₂₂ and Gd@C₈₂(OH)₂₂. Of particular importance, these fullerene derivatives can neutralize all physiologically relevant ROS and RNS, promising great potential in biomedical applications.

Generally, carbon dots (CDs) usually have an average particle size of 2–8 nm, and they have been widely used in biomedical fields due to their good photochemical properties, biocompatibility, as well as stability. Besides the bioimaging applications based on the fascinating fluorescence performance, some CDs have also been employed to treat oxidative stress-related diseases because of their great ROS scavenging ability. For instance, CDs prepared by using gynostemma and garlic as carbon source have been successfully synthesized (Figure 1B) (Wei et al., 2019). These CDs can efficiently eliminate excess ROS in both Hela cells and zebrafish. In another study, phenylenediamine-based CDs have been well designed and constructed for the treatment of acute kidney injury. The ultra-small size can facilitate the CDs to penetrate the glomerular filtration barrier and present the antioxidant properties at the kidney target (Figure 1C) (Gao et al., 2020). Since the various origins of carbon have been reported, it has provided an excellent demonstration for the “bottom-to-top” strategy. However, the mechanism of the antioxidant effect is rarely elucidated. Besides the precursor selection method mentioned above, some agents are used to enhance the antioxidant ability. A kind of CDs made from glutathione and citric acid via hydrothermal method has been designed with the ability to eliminate various free radicals including DPPH· (1,1-diphenyl-2-trinitro phenylhydrazine free radicals, a kind of experimental RNS), ·OH, and O₂·^- (Figure 1D) (Wang et al., 2020a). In addition, metallic heteroatom selenium has been doped into the CDs to fulfill the need for OH scavenging and imaging at the same time (Figure 1E) (Li F. et al., 2017).

As a typical representative of CDs, graphene quantum dots (GQDs) are well researched because of their low toxicity and unique structure. Researchers have created GQDs with antioxidant characteristics, which can efficiently scavenge free radicals and protect cells from oxidative damage. They say ROS was eliminated via surface imperfections and unpaired electrons. Furthermore, the π-conjugated nature facilitated electron transformation and storage (Chong et al., 2016). Based on this theory, phenol-like group functionalized GQDs were rationally designed and well proved to be a better antioxidant in the acute kidney injury model (Figure 2A) (Wang et al., 2020b). Other attempts to improve scavenging results have been made, such as the use of phosphorus-doped GQDs in the efficient elimination of DPPH and ·OH (Li Y. et al., 2017).

Carbon nanotubes (CNTs) are seamless cylinders of rolled-up graphene sheets with distinct intrinsic characteristics, which can be divided into single-wall and multiwall carbon nanotubes, with diameters ranging from 0.4 to 2.5 nm and a few nanometers to 100 nm, respectively. CNTs are believed to be a radical scavenger due to their exceptional electron donation and acceptability abilities acquired from conjugated carbon double bonds. Researchers demonstrate that pristine single-walled CNTs and phenolic-functionalized CNTs are powerful antioxidants (Lucente-Schultz et al., 2009). According to another study, two types of carbon nanotubes with varying thicknesses and lengths exhibit comparable free radical scavenging efficacy. CNTs with smaller diameters and shorter lengths have been shown to be more poisonous and capable of causing inflammation. In another study, the effects of carbon nanotube length, diameter, and chirality on their ability to scavenge free radicals are calculated theoretically (Galano, 2009). According to previous studies, the length and chirality of CNTs usually reveal no effect on antioxidant efficacy. The antioxidant activity of armchair nanotubes can be more affected by changes in tube diameter. Aside from physical properties, both amine modification and polydopamine modification can improve the antioxidant activities of CNTs, as demonstrated in stroke and skin models (Lee et al., 2011; Liang et al., 2019). The location of defects in the material also influences their ability to scavenge free radicals. Methods like ball milling, benzoyl peroxide, and acid treatment can consecutively create defect sites, increasing free radical scavenging ability, whereas microwave treatment repair flaws. Significantly, extended microwave time can extremely reduce fault locations and free radical capabilities (Shieh and Wang, 2014).

Since the first discovery of graphene (G) in 2004, a number of its derivatives, from graphene oxide (GO) to reduced graphene oxide (RGO), have been well investigated in various fields. The obvious difference between G and GO is the addition of oxygen atoms bound to the carbon scaffold. As a result, G is hydrophobic in nature, whereas GO is hydrophilic, which is more applicable in vivo. RGO is reported to react with DPPH·, O₂ ^·-, and OH. The ability to clear OH has been ranked as high as few-layer graphene, GO, and RGO. These results indicate that the primary active sites are highly associated with the pristine graphenic network rather than oxygen-containing functional groups (Qiu et al., 2014; Suresh et al., 2015). In addition, the oxidation resistance of G is also solved through its use as a template to enhance the oxidation activity of molecules of clusters. Huang et al. have reported that GO-Se nanocomposites with excellent GPx-like properties can efficiently protect cells against oxidative stress in vitro (Figure 2B) (Huang et al., 2017).

As a new 2D form of carbon, graphdiyne (GDY) is only one atom thick. Owing to the presence of its good sp- and sp²-hybridized carbon atoms, evenly spaced pores, high conjugation, and unique electronic, physical, and chemical properties, a lot of work has been done to find ways to use it. It is a 2D periodic structure whose fundamental structural unit is a big triangular ring containing 18 carbon atoms. Due to the unique structure of GDY, it has been proved that GDY usually exhibits better performance and higher stability than other carbon-based materials in various practical applications including the fields of energy and biomedicine. For the scavenging free radicals usages, bovine serum albumin (BSA)-modified GDYs have been used as a high-performance radioprotector (Figure 2C) (Xie et al., 2020). These BSA-modified GDYs hold a strong free radical scavenging ability including O₂ ^·- and OH. By eliminating intracellular ROS, BSA-modified GDYs can extremely reduce DNA damage and protect major organs from radiation-induced damage in vivo. In addition, GDYs can be doped into sodium hyaluronate hydrogel to form nano-graphdiyne hydrogels (Xie et al., 2022). These well-prepared graphdiyne-contained hydrogels not only exhibit great broad-spectrum free radical scavenging activity, but also process admirable physically shielding function against low-energy X-ray, which can be used for the external skin radioprotection. Compared to G and its derivatives, GDYs and their derivatives seem to hold better free radical scavenging activity in biomedical fields, which can be researched more in the future.