Green Approaches to Carbon Nanostructure-Based Biomaterials

applied sciences Review Green Approaches to Carbon Nanostructure-Based Biomaterials Simone Adorinni 1 , Maria C. Cringoli 1,2 , Siglinda Perathoner 3,4 , Paolo Fornasiero 1,2,5 Silvia Marchesan 1,2, * 1 2 3 4 5 * and Chemical and Pharmaceutical Sciences Department, University of Trieste, 34127 Trieste, Italy; [email protected] (S.A.); [email protected] (M.C.C.); [email protected] (P.F.) INSTM, University of Trieste, 34127 Trieste, Italy Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, University of Messina, 98168 Messina, Italy; [email protected] INSTM, University of Messina, 98168 Messina, Italy Istituto di Chimica dei Composti Organometallici, Consiglio Nazionale delle Ricerche (ICCOM-CNR), 34127 Trieste, Italy Correspondence: [email protected] Abstract: The family of carbon nanostructures comprises several members, such as fullerenes, nanoonions, nanodots, nanodiamonds, nanohorns, nanotubes, and graphene-based materials. Their unique electronic properties have attracted great interest for their highly innovative potential in nanomedicine. However, their hydrophobic nature often requires organic solvents for their dispersibility and processing. In this review, we describe the green approaches that have been developed to produce and functionalize carbon nanomaterials for biomedical applications, with a special focus on the very latest reports.



 Keywords: carbon nanostructures; graphene; carbon nanotubes; carbon nanodots; nanodiamonds; nanomaterials; biomaterials Citation: Adorinni, S.; Cringoli, M.C.; Perathoner, S.; Fornasiero, P.; Marchesan, S. Green Approaches to Carbon Nanostructure-Based Biomaterials. Appl. Sci. 2021, 11, 2490. https://doi.org/10.3390/app11062490 Academic Editor: Greta Varchi Received: 23 February 2021 Accepted: 5 March 2021 Published: 11 March 2021 Publisher’s Note: MDPI stays neutral 1. Introduction The family of carbon nanostructures (Figure 1) comprises of many different members that generally share the common feature of being composed of carbon atoms, covalently bound in a sp2 hexagonal lattice, although exceptions exist [1]. The two-dimensional (2D)-sheet of graphene can be considered as a universal building block, which, depending on how it is folded, can give rise to 0D fullerenes [2], 1D single-wall [3] or multi-wall [4] carbon nanotubes (CNTs), or 2D-graphene-based materials [5]. Other nanostructures comprise nano-onions (CNOs) [6], nanohorns (CNHs) [7], nanocones, and nanodiscs [8]. Nanodiamonds (NDs) differ for they contain a large portion of sp3 carbon atoms [9]. More recently, carbon dots have acquired increasing attention [10]. Furthermore, carbon nanostructures can be assembled together in superstructures [11] and 3D-materials [12]. with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Figure 1. Carbon nanostructures discussed in this review (not to scale). The nano-onion schematic structure is reproduced with permission from [13], copyright ©1995, Elsevier. Appl. Sci. 2021, 11, 2490. https://doi.org/10.3390/app11062490 https://www.mdpi.com/journal/applsci Appl. Sci. 2021, 11, 2490 2 of 20 Each of these components has its own unique properties related to the specific morphology, size, and reactivity. They generally feature very interesting electronic conductivity, high mechanical strength, low density, as well as the ability to undergo chemical functionalization to further tune their properties as needed for the intended application. It is thus not surprising that many reviews already exist on their clinical applications [14] in biomedicine [15–17] and, above all, on their potential use in oncology [18], such as innovative components in cancer theranostics [19] and cancer therapy [20], thanks to their ability to target the tumor micro-environment [21]. Indeed, the possibility to use them not only as vehicles for drug delivery [22], but also for innovative imaging [23] and biosensing [24], makes them ideal candidates for innovative theranostics [25,26]. Research is also very active on their applications to target diseases other than cancer, such as atherosclerosis [27], and infections [28], including the recent fight against coronaviruses [29]. Further areas of intense investigation include tissue engineering [30], in particular to reconstruct the heart [31] and to re-establish neural connections [32], due to their demonstrated ability to boost the electrical activity of conductive tissue [33] and stimulate nerve growth [34]. Finally, there has been increased interest in their electron-conductive abilities, to develop innovative wearable electronics [35]. Interactions between carbon nanomaterials and biomolecules, especially DNA [36] and proteins [37], are the object of many investigations, due to their role in determining the dynamic structure of the biomolecular corona [38], which ultimately affects the response in vivo [39], e.g., the biodistribution [40], the immune response [41], for instance mediated by neutrophils [42], and, thus, the biodegradation [43]. Despite decades of research efforts in these sectors, there are still many concerns regarding carbon nanostructure toxicity [44,45] and immunogenicity [46], also due to the high heterogeneity of this class of materials, which present both unexploited opportunities and unresolved challenges [47] in nanomedicine. In particular, one of the latter regards the large-scale production for mainstream applications [48], considering the current emergency we are facing, in terms of preservation of the environment, especially the development and implementation of green routes for their sustainable production. Therefore, in light of the vastness and complexity of the topic of carbon nanomaterials for biomedical applications, this concise review aims to cover only the most recent advances in the nanomedicine area that describe green chemical routes for their preparation and chemical modifications, in the hope that it will inspire scientists that enter this area towards more environmentally conscious choices for their chemical procedures. 2. Green Routes to Prepare Carbon Nanomaterials for Biomedical Applications In recent years, researchers have been paying more attention to green routes for the production of carbon-based nanomaterials, as well as for biomedical applications, and the topic was reviewed recently for specific types of nanostructures, especially carbon quantum dots (CQDs) [49,50]. However, this is a very active field of prolific research and many new reports continue to appear at a fast pace in the literature. Therefore, in this work, we will focus on the most recent examples that will be organized based on the type of nanostructure produced, in particular fullerenes, nano-onions, CQDs, nanodiamonds, nanohorns, CNTs, and 2D-graphene-based nanomaterials. Table 1 details the type of nanostructure, green route employed, carbon source, and solvent used, and the envisaged application for the most recent reports that discuss the preparation of various types of carbon nanomaterials in their pristine form, as well as their reduction and oxidation, which are often the first step to fine-tune their properties for biological uses. Appl. Sci. 2021, 11, 2490 3 of 20 Table 1. Recent examples of green methods to produce carbon nanostructures, their oxidized and reduced forms, suitable for biomedical applications. Carbon Nanostructure Green Route Carbon Source Solvent Application Reference Fullerenes 1 Catalytic thermal decomposition Plastic waste n.a. n.a. [51] Nano-onions Carbonization Hydrothermal Tomatoes Citric acid Water Water Theranostics n.a. [52] [53] Calcination Gynostemma plant Water Electrochemistry Graphite Water/ethanol Gamma irradiation Graphite Water/ethanol Hydrothermal Hydrothermal Chitosan Cyanobacteria Water Water Hydrothermal Fruit flesh Water Hydrothermal Fruit juice Water Hydrothermal Fruit peel Water Hydrothermal Fruit waste Water/ethanol Hydrothermal Green tea Water Hydrothermal Red cabbage Water Hydrothermal Sugarcane bagasse pulp Water Hydrothermal Wheat straw Water Microwave Cellulose Water Microwave Roasted chickpeas Water Pyrolysis Pyrolysis Sand bath Sonochemical Citric acid Zingiberis rhizoma Fruit peel Gelatin Laser ablation CQDs NDs 2 Bioimaging Antioxidant Radioimaging Photodynamic therapy pH sensing Composites Ag+ sensing Bioimaging Bioimaging Hg++ sensing Fe+++ sensing Bioimaging Fe+++ sensing Photodynamic therapy Fluorescent ink Antioxidant Antibacterial [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] Water Water Water Water Bioimaging F− sensing Biomaterials Bioimaging Fe+++ sensing Hg++ sensing Analgesic Bioimaging Bioimaging [69] [70] [71] [72] Coal Ethanol n.a. [73] [66] [67] [68] Microplasma jet NDs Water n.a. [74] oxidized CNHs 2 UV/H2 O2 oxidation CNHs Water Drug delivery [75] oxidized CNTs 2 UV-ozone CNT fibers n.a. Electronics GO 2,3 Electrochemical Photoelectrochemical Graphite Graphite Acidic water Water (Bio)materials (Bio)materials [76] [77] GO 3 Water n.a. [78] rGO 2,3 Mushroom-extracted reductant Cysteine reductant Ascorbic acid reductant GO 3 GO 3 Water/ethanol Water Drug delivery Neuroscience [79] [80] oxidized NDs 1 magnetic derivative composite. 2 the green route refers solely to the functionalization of the nanocarbon and not the preparation of the carbon nanostructure scaffold used as starting material. 3 (r)GO = (reduced) graphene oxide. 2.1. Fullerenes Fullerenes are spheroidal molecules composed solely of carbon, of which the most widely known is C60 , composed of 60 carbon atoms. Their nanosize and peculiar electronic properties rendered them the subject of many investigations for potential uses in nanomedicine [81], including drug delivery [82], photodynamic [83], antioxidant [84,85], and even antiviral [86] therapy. Appl. Sci. 2021, 11, 2490 4 of 20 Fullerenes can be synthesized by many methods, which mainly involve the vaporization of graphite or similar carbon sources, and that include arc-evaporation, pyrolysis, radio-frequency plasma, or laser ablation. Moreover, fullerenes purification requires large volumes of organic solvents due to their generally low solubility [81]. Therefore, the development of green procedures for their preparation is not at all trivial. However, the use of microwaves [87] can be beneficial in reducing reaction times and temperatures, although even this convenient development has not solved the many challenges faced by the industry to produce fullerenes at a low cost [88]. It is worth noting that fullerenes need to be derivatized to be water-soluble in appreciable concentrations for biomedical applications; therefore, opportunities for the green synthesis of fullerenes may lie in the preparation of those derivatives. For instance, hydrophilic polydopamine and glutathione were used to solubilize fullerenes by simple mixing in water, followed by dialysis and freeze-drying, to then study their antioxidant activity [89]. Sonochemical treatment in water of a mixture of fullerene and gallium oxide yielded nanostructured hybrids with potential applications in the field of sensing [90]. While these methods simply focus on derivatization without addressing the synthesis of the fullerene core structure, a recent development consisted of the catalytic conversion of plastic waste into a magnetic fullerene-based composite, thanks to the key role played by ferrocene, which acted both as a catalyst and magnetic nanoparticle precursor [51]. 2.2. Carbon Nano-Onions (CNOs) CNOs are multi-layered fullerenes that have also attracted attention for potential biomedical uses that range from bioimaging and sensing [6,91] to drug delivery [92], also thanks to a good biocompatibility profile, as shown in vertebrate models [93,94]. Furthermore, for certain applications, they can surpass other carbon nanostructures, as shown for instance by their promising performance as terahertz contrast agents for breast cancer imaging [95]. Their chemical structure similarity to fullerenes poses analogous challenges for their synthesis as described in the previous section. Nevertheless, in this case, there are efforts towards the development of green routes for their production and modification. Tomatoes have been thermally decomposed in alkaline conditions to this end, and lycopene was hypothesized as a possible carbon source [52]. Citric acid was also successfully used as a starting material in a hydrothermal route to CNOs (Figure 2) [53]. Figure 2. Hydrothermal treatment of (a) citric acid (a) yields comprise nano-onions (CNOs), shown Figure 2. Hydrothermal treatment of citric acid yields comprise nano-onions (CNOs), as shown by TEM (b).asAdapted with permission from [53], Copyright © 2020 Wiley-VCH GmbH. By contrast, CNO functionalization typically requires organic solvents and harsh conditions at least during the initial steps, for instance, to oxidize defective sites into carboxylic groups for further derivatization [96]. Then, other functionalities can be appended Appl. Sci. 2021, 11, 2490 5 of 20 under mild conditions, for instance, as shown for chitosan and poly(vinyl alcohol) to yield composite biomaterials for tissue engineering [97], or for gelatin to yield hydrogels for drug delivery [98], or for protein fibrils to improve CNO biocompatibility [99]. Alternatively, pristine CNOs can be non-covalently functionalized with water-soluble species in aqueous environments, as shown for hyaluronic acid-phospholipid conjugates that allowed the selective targeting of cancer cells for drug delivery [100]. 2.3. Carbon Quantum Dots (CQDs) Carbon quantum dots (CQDs) are quasi-spherical nanoparticles characterized by pronounced luminescent properties, thus very appealing for sensing, and, recently, further morphologies have been attained to fine-tune their luminescent profiles [101], which depend also on the carbon source used [102]. Other applications include photodynamic (antibacterial) therapy [56,103,104], radiolabeled imaging [55], various forms of bioimaging [60,71], and sensing [59–61,69]. They have also been investigated for their antioxidant activity against radical oxygen species (ROS) mediated cell damage [54,64], and as drug delivery agents [105]. Graphene quantum dots (GQDs), which consist of nano-sized graphene monolayers that exhibit quantum confinement, can be produced in a variety of methods, of which the most popular are pyrolysis [69,70] and hydrothermal [57–61,63,64] routes. Other methods that could be carried out at lower temperatures have attracted attention, especially using microwaves [67,68,106], but also ultrasound-assisted approaches [72]. Recently, an electrochemical green approach was developed that employed water and ethanol as solvents [55]. In this case, the dots were also radiolabeled with technetium-99m for imaging purposes, and in vivo experiments overall revealed a good profile in terms of biosafety, although some signs of mutagenic activity were noted [55]. Finally, GQDs were produced by UV-triggered radical polymerization of oxygen-containing aromatic compounds in water for bioimaging, producing just water and carbon dioxide as side-products [107]. A plethora of natural sources have been recently reported for the green synthesis of CQDs. Citric acid and penicillamine underwent pyrolysis to yield nitrogen- and sulfur co-doped CQDs that could detect mercury ions in living cells by means of fluorescence quenching [69]. Concerning plants, and plant derived-materials, various carbon sources have been used. They include fruit parts, such as seed extract [108], flesh [59], peel [61,71], juice [60], and fruit waste [62]. Alternatively, hemicellulose [109] or cellulose, combined with caffeic acid as a green reducing agent [67], or other plant parts, such as Gynostemma plant [54], red cabbage [64], palm-derived powder [110], green tea [63], mint [111], or turmeric [104] leaves, sunflower seeds [112], roasted chickpeas [68], wheat straw [66], soybean residues [113], and sandalwood powder [114]. Some of these carbon sources have been used with the prospect of recycling household kitchen waste, although in line of principle, the same concept could be applied to industrial waste. With this idea in mind, sugarcane bagasse pulp found a second use to be converted in antibacterial CQDs [65]. In the majority of cases, CQDs are used in solution, as they were shown to enter cells by endocytosis and could be tailored to target specific subcellular organelles [108]. However, more research is emerging on their use in composites, for instance to reinforce films for tissue engineering applications [67], to yield luminescent hydrogels [115], or UV-responsive smart (bio)materials [58,116], and antibacterial composites [117]. 2.4. Nanodiamonds (NDs) NDs differ from many of the other carbon nanostructures owing to the presence of a large number of sp3 -hybridized carbon atoms, as the name suggests. However, they do also feature sp2 carbon atoms [118] and various oxygen-containing functional groups on their surface (Figure 3) that can be exploited for functionalization [119], as recently reviewed [120]. Appl. Sci. 2021, 11, 2490 6 of 20 Figure 3. Blended atomistic model (left) and high-resolution TEM micrograph (right) of a nanodiamond (ND) to show its typical chemical structure. Reprinted from [121], copyright © 2015, with permission from Elsevier. Their production typically requires high temperatures and pressures to obtain sp3 hybridization, such as those occurring in detonations. Other methods include chemical vapor deposition and milling of microsized diamonds [9]. Recently, a laser ablation route has been reported as a green alternative due to the possibility to carry it out at ambient temperatures [73]. Due to their low reactivity, functionalization is usually carried out in organic solvents under harsh conditions, or in the gas-phase, and can be promoted by microwaves, plasma, or UV irradiation [120]. Very few reports exist on their functionalization under green conditions. Often, the first step involves ND oxidation by strong-acid treatment [122], to provide functional groups for further derivatization. However, oxidation can also be attained through a green route, using atmospheric-pressure radio-frequency microplasma jet to deliver aqueous oxygen radicals to NDs suspended in water [74]. Then, further functionalization can occur under a variety of classical conditions, for instance to coat NDs with a suitable (bio)polymer for colloidal stability and improved biocompatibility [123]. In the majority of cases, non-environmentally friendly solvents are used, such as dimethylformamide; however, oxidized NDs can be further derivatized also in water [124], or other environmentally-friendly solvents, such as acetone and alcohols, as required for the other reagents, e.g., drugs [125]. Aqueous couplings were performed in this manner to attach a fluorescent protein and CRISPR-Cas9 components for gene editing [122], or to bind polyethylene glycol, and a lanthanide complex for enhanced bioimaging [126]. Alternatively, other useful functional groups for derivatization are alkynes to perform click-chemistry. In one example, NDs were first reacted with glycidol and glycidyl propargyl ether, which both served as reagents and solvents, to then allow the copper-catalyzed click reaction in an aqueous environment with a fluorophore for bioimaging [127]. In a similar approach, the click reaction was performed with a precursor of nitroxide radicals, which could be generated by sonochemical-promoted air oxidation, for redox sensing [128]. Mussel-inspired bioadhesives have also been effectively applied to coat and functionalize NDs in water, so that further molecules could be appended, such as polyethylene glycol polymer for colloidal stability, or DNA for particle tracking (Figure 4) [129]. Another biocompatible coating is mesoporous silica, which can be formed on the surface of NDs in aqueous conditions and allows to include a variety of functional groups, for instance for Appl. Sci. 2021, 11, 2490 7 of 20 the convenient grafting of a hydrogel polymer shell and metal nanoparticles for advanced sensing techniques [130]. Figure 4. Dopamine can be polymerized in water to coat NDs and provide functional groups for the subsequent anchoring of polymers and biomolecules for imaging and detection. Adapted with permission from [129], copyright © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. Finally, NDs can be simply used as scaffolds to adsorb other molecular species, as shown for a hydrophobic magnetic-resonance contrast agent that required a mixture of DMSO and water to react with NDs, while the resulting product was water-soluble and could be tested for imaging [131]. They have been proposed as antibacterials [132,133], for regenerative medicine [134], drug delivery [135–137], bioimaging [136,138,139], cancer therapy [137,140,141], theranostics [142,143], and ultrasensitive diagnostics [144]. For many – to be used in composites [145,146]. Their ability of these applications, they were envisaged to pass the blood–brain barrier has also attracted attention for targeting the brain, to address existing challenges in the treatment of neurodegenerative diseases [147]. Their rather inert chemical nature – renders their functionalization quite challenging, but with the benefit of a good biocompatibility profile [138], depending also on the type of functional groups that they display [148]. 2.5. Carbon Nanohorns (CNHs) “ Carbon nanohorns (CNHs) or nanocones consist of short cones of sp2 carbon atoms that aggregate into clusters of ca. 100 nm diameter and can be mainly of two types, i.e., “dahlia-like”, when the cones protrude from the aggregate, or “bud-like” when they do not (Figure 5). They are produced by arc-discharge, laser ablation, or joule heating, from graphite [7], although greener alternatives at lower temperatures are continually sought Similar to the other carbon nanomaterials, they have been proposed for drug like”, when [149]. the cones protrude from the aggregate, or “bud like” when they do delivery [150], sensing [151], theranostics [152], and as components of nanocomposites for phosphoproteomics in cancer diagnosis [153], or for cancer treatment [154], or to yield patches for topical applications on skin [155]. Appl. Sci. 2021, 11, 2490 8 of 20 Figure 5. TEM micrographs of (a) dahlia-like and (b) bud-like carbon nanohorns. Functionalization is required to avoid further aggregation into larger clusters and ensure homogeneous dispersions in aqueous environments. It is typically carried out similarly to the other nanocarbons, with the most popular route being oxidation (for instance in air at high temperatures) and subsequent coupling to other (bio)molecules in water, as shown with a fluorophore–albumin conjugate to ensure colloidal stability and ease of tracking for bone-tissue regeneration studies [156]. Alternatively, treatment with hydrogen peroxide at 100 ◦ C under UV-irradiation oxidizes CNHs, which then can be purified in water and stabilized with albumin [157], or attached with fluorophore-protein conjugates in aqueous environments, as shown in studies that tracked their cell entrance by endocytosis [75]. However, the most common route to oxidize CNHs is by treatment with nitric acid under mild heating [158], thanks to their high reactivity ensured by the highly curved, thus strained, cone tips. Once carboxylic acid groups have been installed, they can be coupled in aqueous environments to smart fluorophores, which allowed to confirm the endocytic entrance of CNHs into cells [159]. Many other covalent functionalization approaches exist. Among these, 1,3-dipolar cycloaddition of an azomethine ylide, generated in situ from an amino acid and an aldehyde, can be performed in solvent-free conditions in a microwave reactor, for instance to attach oligothiophene to allow Surface-Enhanced Raman Spectroscopy (SERS) imaging [160]. Non-covalent functionalization is also a popular approach. For instance, a simple sonochemical treatment of CNHs with a dye [161] or a natural photosensitizer [162] promoted adsorption onto the CNH surface, thanks to hydrophobic interactions, for combined multimodal imaging, photodynamic, and photothermal treatment of cancer cells, as shown in Figure 6. Similarly, when CNHs were added to albumin under sonication, a stable dispersion could be achieved at physiological conditions [163]. When compared against CNTs, interestingly, CNHs were shown to be more biocompatible due to their reduced ability to adsorb proteins on their surface [163], analogously to what observed for a self-assembling tripeptide [164]. Finally, colloidal stability of CNHs can be ensured also by surfactants, such as the biocompatible pluronic, by simple mixing in water, as envisaged to restore the mechanical integrity of tendon tissues after a sprain [165]. Appl. Sci. 2021, 11, 2490 9 of 20 Figure 6. Sonochemical treatment ensures dye adsorption onto CNH surface for theranostics, i.e., multi-modal imaging, photodynamic therapy (PDT), and photothermal therapy (PTT). Reproduced with permission from [161], copyright © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. 2.6. Carbon Nanotubes (CNTs) CNTs can be considered as sheets of graphene rolled up in a tube, and comprise mainly single-walled CNTs or multi-walled CNTs, depending on the number of sheets that compose their walls. Similar to the other nanostructures, they have been noted as promising materials to innovate in the biochemical field. However, their morphological similarity to asbestos fibers has posed many barriers for their applications, despite the fact that functionalization can alleviate their toxicity, as recently reviewed [41]. In 2019, CNTs have been added to the ChemSec SIN (Substitute It Now) list, in light of the studies on their toxicity and resistance to biodegradation [166]. This prompted a strong response from the academic community active on CNT research that feared further obstacles to innovation, in which it was noted that toxicity was related to a specific type of CNT, and this class of nanomaterials is very diverse, as the biocompatibility profiles depend on a plethora of factors, which include functionalization and route of administration [167–169]. Indeed, CNTs have shown a unique ability to boost the activity of conductive cells [33], demonstrating an unmissable opportunity to regenerate the cardiac [170] and nerve tissues [34]. Furthermore, their high mechanical resilience and low mass density is promising for orthopedic applications [171]. CNT-coated surfaces effectively stimulated osteogenic differentiation of mesenchymal stem cells, which adhered and spread, with numerous visible focal adhesion and actin stress fibers, as shown in Figure 7 [172]. Besides tissue engineering [173], CNTs have also been proposed to attain antimicrobial and anti-adhesive surfaces for medical applications [174]. Their bioconjugation can serve a variety of innovative applications that span from tissue engineering, to sensing and wearable electronics [175], and, in general, to prepare innovative biomedical electrodes [176]. Their biodegradation is possible, depending also on experimental conditions, route of degradation, and CNT functionalization [43]. Appl. Sci. 2021, 11, 2490 10 of 20 Figure 7. Stem cells (nuclei stained in blue) adhere and spread onto single-walled (SWNT, left) or multi-walled (MWNT, right) CNT-coated surfaces with multiple focal adhesions (green with vinculin-staining) and actin fibers (red). Reproduced from [172]. As discussed above for other nanostructures, also in the case of CNTs, oxidation is often the first step for their biological application to achieve good dispersibility in water, and this is typically obtained by acid treatment, as shown in a recent study where oxidized CNTs demonstrated antibacterial activity [177]. The process can be carried out also in a microwave oven [178]. However, this kind of treatment requires extensive washings, and greener alternatives include gas-phase methods that use radical oxygen species generated by UV irradiation in air [179]. Once carboxylic acid groups have been installed on CNTs, several subsequent functionalization routes can be undertaken, as needed. For instance, the cationic photosensitizer malachite green could be adsorbed by electrostatic and hydrophobic interactions by simple ultrasonication in water, for antibacterial photodynamic therapy [180]. With an analogous procedure, hyaluronic acid was added to CNTs and the resulting materials were sterilized by gamma irradiation before being used for bone healing [181]. Moreover, without ultrasounds, simple mixing with doxorubicin in phosphate buffered saline solution allowed for the drug adsorption onto CNTs [182]; doxorubicin sustained release by CNTs is indeed a hot topic of research in cancer therapy [183]. Alternatively, the carboxylic acid groups can be covalently coupled to biomolecules in water, as shown for ovalbumin to boost immune response to antigen presentation for vaccine development [178]. With an analogous approach, oxidized CNTs were coupled to dopamine to promote the mineralization with hydroxyapatite, and CNT electronic properties were exploited to achieve directional alignment through agarose gel electrophoresis to form scaffolds with collagen, which promoted the healing of bone defects in vivo [184]. Non-covalent CNT functionalization is also a popular route, as it does not disrupt their electronic properties. Use of ultrasounds promoted the wrapping of CNTs by polyethylene glycol-pyrene polymer to achieve stable dispersions to induce apoptosis of colon cancer cells by applying nanosecond electric pulses, which affected calcium flux within cells [185]. Simple mixing of CNTs with cationic polyamidoamine polymer and anionic dsRNA, with ultrasonication at room temperature, provided coated CNTs for gene knockdown interventions [186]. Similarly, sonication of CNTs with DNA in saline solutions, followed by purification using polymers, was effective to yield dispersible CNTs that showed very good short-term and long-term biocompatibility in vivo [187]. DNA–CNT complexes were also used in hydrogel composites with silica nanoparticles to deliver doxorubicin [188]. When dispersed with Triton within a glycol-chitosan hydrogel, CNTs promoted cell migration and recruitment, with potential applications in wound healing [189]. Conductive composites for potential applications in sensing were obtained by mixing CNTs with soy lecithin, natural rubber, and the green solvent methyl isobutyl ketone in a homogenizer at high pressure [190]. Appl. Sci. 2021, 11, 2490 11 of 20 2.7. Graphene-Based Materials The class of graphene-based materials is vast and diverse, thus it is important to be aware of the specific type of structure under study, and how it may differ relative to existing literature on the topic [191]. Graphene has captured scientists’ imagination for a variety of uses in medicine, yet there are still unsolved challenges to its wide implementation on a global industrial scale to widely reach the market, although steady progress is being made in this direction [192]. Among the many applications, those related to antibacterial properties are highly studied [193]. The unique properties due to the 2D nature of graphenebased materials are of particular importance for uses in sensing [194]. These materials have been widely studied for their biocompatibility and the data gathered thus far is promising, although, given the wide diversity of graphene-based materials, it is desirable to move from descriptive to predictive toxicology [5]. In particular, formation of a biomolecular corona on graphene-based materials and its consequences on biodistribution and cytocompatibility has been recently reviewed [39]. Graphene can be produced in a variety of ways, of which the most popular include graphite exfoliation in the presence of various dispersants (Figure 8). However, to ensure good water dispersibility, graphene is typically oxidized to graphene oxide (GO), in a process for which green alternatives are continually sought [195]. In particular, electrochemical oxidation of graphite in acidic water was efficient within seconds to yield GO-based conductive materials [76]. The process could be further enhanced by exploiting synergy with photochemistry [77]. Figure 8. Graphene dispersed in water can be obtained from graphite through exfoliation with a variety of dispersing agents. Reproduced from [192], published by the Royal Society of Chemistry. GO is often reduced for enhanced electronic properties, and quite a few green approaches for this step have been recently reported. For example, GO was efficiently reduced by natural polysaccharides extracted from an edible mushroom to yield nanosheets that displayed good biocompatibility up to 0.1 mg/mL [78]. The amino acid cysteine was also effective at reducing GO in ethanol/water solutions with a sonochemical treatment, to yield rGO that was then embedded in a hydrogel for drug delivery [79]. Ascorbic acid provided another example of green reductant for GO to yield nanostructures that were investigated for applications in neuroscience [80]. Once GO or rGO is produced, the material can be further functionalized as described above for the other oxidized carbon nanomorphologies, covalently or non-covalently, as shown for instance for the bioconjugation of a peptide that benefited from enhanced antibacterial activity and reduced hemolytic effects [196]. Green routes towards inclusion of GO into (bio)composites are also receiving attention [197]. Appl. Sci. 2021, 11, 2490 12 of 20 3. Conclusions Carbon nanomaterials come in different shapes and sizes, each one with its own peculiar opportunities and challenges to innovate in nanomedicine. Over the last decades, they have been widely investigated for a variety of applications as described in this review, and in recent years, more attention has been paid to green routes towards their production and modification. Among the various approaches described in this review, the use of microwaves and photochemistry are certainly among the most promising strategies that, in line of principle, could be extended further to many other different types of chemical functionalization. At present, the use UV-generated radicals or UV-H2 O2 mediated oxidations appears particularly attractive, since these are convenient oxidation alternatives to more traditional routes that employ strong acids. Benefits are varied. First, the reaction can be carried out in portable devices with UV-lamps that are widely available. Second, if the reaction is performed in the gas-phase, there will be no liquid or solid waste; hence, no need for extensive washings for product purification. Alternatively, if the reaction is performed in the liquid phase with hydrogen peroxide, there will be benign byproducts. Third, UV-promoted oxidation in the gas-phase was shown to be effective also in preserving the macroscopic morphology of the materials, such as the case of CNT fibers. Electrochemistry is another very promising approach; however, it requires knowledge and equipment that may not be available to all. In many cases, carbon nanomaterials’ limited solubility in polar solvents and reduced reaction yields in green conditions drive scientists to opt, in practice, for the nonenvironmentally friendly protocols. However, the hope is that as more literature is gathered on this interesting topic, the community of scientists willing to adopt and develop greener routes will widen significantly to fully unlock the potential of these innovative materials for the maximum benefit of society and the environment. Author Contributions: Supervision, S.P., P.F., and S.M.; writing—original draft preparation, S.A. and M.C.C.; writing—review and editing, S.P., P.F., and S.M. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by EU H2020 NMBP-SPIRE project, grant no. 820723. Acknowledgments: The authors acknowledge M. Bisiacchi and E. Merlach for their kind technical support. Conflicts of Interest: The authors declare no conflict of interest. References 1. 2. 3. 4. 5. 6. 7. 8. Georgakilas, V.; Perman, J.A.; Tucek, J.; Zboril, R. Broad family of carbon nanoallotropes: Classification, chemistry, and applications of fullerenes, carbon dots, nanotubes, graphene, nanodiamonds, and combined superstructures. Chem. Rev. 2015, 115, 4744–4822. [CrossRef] McHedlov-Petrossyan, N.O. Fullerenes in liquid media: An unsettling intrusion into the solution chemistry. Chem. Rev. 2013, 113, 5149–5193. [CrossRef] Yang, F.; Wang, M.; Zhang, D.; Yang, J.; Zheng, M.; Li, Y. Chirality pure carbon nanotubes: Growth, sorting, and characterization. Chem. Rev. 2020, 120, 2693–2758. [CrossRef] [PubMed] Tasis, D.; Tagmatarchis, N.; Bianco, A.; Prato, M. Chemistry of carbon nanotubes. Chem. Rev. 2006, 106, 1105–1136. [CrossRef] [PubMed] Fadeel, B.; Bussy, C.; Merino, S.; Vázquez, E.; Flahaut, E.; Mouchet, F.; Evariste, L.; Gauthier, L.; Koivisto, A.J.; Vogel, U.; et al. Safety assessment of graphene-based materials: Focus on human health and the environment. ACS Nano 2018, 12, 10582–10620. [CrossRef] Giordani, S.; Camisasca, A.; Maffeis, V. Carbon nano-onions: A valuable class of carbon nanomaterials in biomedicine. Curr. Med. Chem. 2019, 26, 6915–6929. [CrossRef] [PubMed] Karousis, N.; Suarez-Martinez, I.; Ewels, C.P.; Tagmatarchis, N. Structure, properties, functionalization, and applications of carbon nanohorns. Chem. Rev. 2016, 116, 4850–4883. [CrossRef] [PubMed] Lin, C.-T.; Lee, C.-Y.; Chiu, H.-T.; Chin, T.-S. Graphene structure in carbon nanocones and nanodiscs. Langmuir 2007, 23, 12806–12810. [CrossRef] Appl. Sci. 2021, 11, 2490 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 13 of 20 Basso, L.; Cazzanelli, M.; Orlandi, M.; Miotello, A. Nanodiamonds: Synthesis and application in sensing, catalysis, and the possible connection with some processes occurring in space. Appl. Sci. 2020, 10, 4094. [CrossRef] Liu, J.; Li, R.; Yang, B. Carbon dots: A new type of carbon-based nanomaterial with wide applications. ACS Cent. Sci. 2020, 6, 2179–2195. [CrossRef] Li, Z.; Liu, Z.; Sun, H.; Gao, C. Superstructured assembly of nanocarbons: Fullerenes, nanotubes, and graphene. Chem. Rev. 2015, 115, 7046–7117. [CrossRef] Sun, Z.; Fang, S.; Hu, Y.H. 3D Graphene materials: From understanding to design and synthesis control. Chem. Rev. 2020, 120, 10336–10453. [CrossRef] Ugarte, D. Onion-like graphitic particles. Carbon 1995, 33, 989–993. [CrossRef] Loh, K.P.; Ho, D.; Chiu, G.N.C.; Leong, D.T.; Pastorin, G.; Chow, E.K. Clinical applications of carbon nanomaterials in diagnostics and therapy. Adv. Mater. 2018, 30, e1802368. [CrossRef] Plonska-Brzezinska, M.E. Carbon nanomaterials: Perspective of their applications in biomedicine. Curr. Med. Chem. 2019, 26, 6832–6833. [CrossRef] Gupta, T.K.; Budarapu, P.R.; Chappidi, S.R.; YB, S.S.; Paggi, M.; Bordas, S.P. Advances in carbon based nanomaterials for bio-medical applications. Curr. Med. Chem. 2019, 26, 6851–6877. [CrossRef] [PubMed] Teradal, N.L.; Jelinek, R. Carbon nanomaterials in biological studies and biomedicine. Adv. Healthc. Mater. 2017, 6. [CrossRef] [PubMed] Mehra, N.K.; Jain, A.K.; Nahar, M. Carbon nanomaterials in oncology: An expanding horizon. Drug Discov. Today 2018, 23, 1016–1025. [CrossRef] [PubMed] Augustine, S.; Singh, J.; Srivastava, M.; Sharma, M.; Das, A.; Malhotra, B.D. Recent advances in carbon based nanosystems for cancer theranostics. Biomater. Sci. 2017, 5, 901–952. [CrossRef] Hosnedlova, B.; Kepinska, M.; Fernandez, C.; Peng, Q.; Ruttkay-Nedecky, B.; Milnerowicz, H.; Kizek, R. Carbon nanomaterials for targeted cancer therapy drugs: A critical review. Chem. Rec. 2019, 19, 502–522. [CrossRef] Saleem, J.; Wang, L.; Chen, C. Carbon-based nanomaterials for cancer therapy via targeting tumor microenvironment. Adv. Healthc. Mater. 2018, 7, e1800525. [CrossRef] Zhao, Q.; Lin, Y.; Han, N.; Li, X.; Geng, H.; Wang, X.; Cui, Y.; Wang, S. Mesoporous carbon nanomaterials in drug delivery and biomedical application. Drug Deliv. 2017, 24, 94–107. [CrossRef] Bartelmess, J.; Quinn, S.J.; Giordani, S. Carbon nanomaterials: Multi-functional agents for biomedical fluorescence and Raman imaging. Chem. Soc. Rev. 2015, 44, 4672–4698. [CrossRef] Sainio, S.; Leppänen, E.; Mynttinen, E.; Palomäki, T.; Wester, N.; Etula, J.; Isoaho, N.; Peltola, E.; Koehne, J.; Meyyappan, M.; et al. Integrating carbon nanomaterials with metals for bio-sensing applications. Mol. Neurobiol. 2020, 57, 179–190. [CrossRef] Kim, M.; Jang, J.; Cha, C. Carbon nanomaterials as versatile platforms for theranostic applications. Drug Discov. Today 2017, 22, 1430–1437. [CrossRef] Mishra, V.; Patil, A.; Thakur, S.; Kesharwani, P. Carbon dots: Emerging theranostic nanoarchitectures. Drug Discov. Today 2018, 23, 1219–1232. [CrossRef] Rezaee, M.; Behnam, B.; Banach, M.; Sahebkar, A. The Yin and Yang of carbon nanomaterials in atherosclerosis. Biotechnol. Adv. 2018, 36, 2232–2247. [CrossRef] Xin, Q.; Shah, H.; Nawaz, A.; Xie, W.; Akram, M.Z.; Batool, A.; Tian, L.; Jan, S.U.; Boddula, R.; Guo, B.; et al. Antibacterial carbon-based nanomaterials. Adv. Mater. 2019, 31, e1804838. [CrossRef] Łoczechin, A.; Séron, K.; Barras, A.; Giovanelli, E.; Belouzard, S.; Chen, Y.T.; Metzler-Nolte, N.; Boukherroub, R.; Dubuisson, J.; Szunerits, S. Functional carbon quantum dots as medical countermeasures to human Coronavirus. ACS Appl. Mater. Interfaces 2019, 11, 42964–42974. [CrossRef] Ku, S.H.; Lee, M.; Park, C.B. Carbon-based nanomaterials for tissue engineering. Adv. Healthc. Mater. 2013, 2, 244–260. [CrossRef] Ashtari, K.; Nazari, H.; Ko, H.; Tebon, P.; Akhshik, M.; Akbari, M.; Alhosseini, S.N.; Mozafari, M.; Mehravi, B.; Soleimani, M.; et al. Electrically conductive nanomaterials for cardiac tissue engineering. Adv. Drug Deliv. Rev. 2019, 144, 162–179. [CrossRef] Carvalho, C.R.; Silva-Correia, J.; Oliveira, J.M.; Reis, R.L. Nanotechnology in peripheral nerve repair and reconstruction. Adv. Drug Deliv. Rev. 2019, 148, 308–343. [CrossRef] [PubMed] Marchesan, S.; Bosi, S.; Alshatwi, A.; Prato, M. Carbon nanotubes for organ regeneration: An electrifying performance. Nano Today 2016, 11, 398–401. [CrossRef] Marchesan, S.; Ballerini, L.; Prato, M. Nanomaterials for stimulating nerve growth. Science 2017, 356, 1010–1011. [CrossRef] Wu, Z.; Wang, Y.; Liu, X.; Lv, C.; Li, Y.; Wei, D.; Liu, Z. Carbon-Nanomaterial-based flexible batteries for wearable electronics. Adv. Mater. 2019, 31, e1800716. [CrossRef] Sun, H.; Ren, J.; Qu, X. Carbon nanomaterials and DNA: From molecular recognition to applications. Acc. Chem. Res. 2016, 49, 461–470. [CrossRef] Marchesan, S.; Prato, M. Under the lens: Carbon nanotube and protein interaction at the nanoscale. Chem. Commun. 2015, 51, 4347–4359. [CrossRef] Pinals, R.L.; Yang, D.; Lui, A.; Cao, W.; Landry, M.P. Corona Exchange dynamics on carbon nanotubes by multiplexed fluorescence monitoring. J. Am. Chem. Soc. 2020, 142, 1254–1264. [CrossRef] Appl. Sci. 2021, 11, 2490 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 14 of 20 Palmieri, V.; Perini, G.; De Spirito, M.; Papi, M. Graphene oxide touches blood: In vivo interactions of bio-coronated 2D materials. Nanoscale Horiz. 2019, 4, 273–290. [CrossRef] Cai, K.; Wang, A.Z.; Yin, L.; Cheng, J. Bio-nano interface: The impact of biological environment on nanomaterials and their delivery properties. J. Control. Release 2017, 263, 211–222. [CrossRef] [PubMed] Marchesan, S.; Kostarelos, K.; Bianco, A.; Prato, M. The winding road for carbon nanotubes in nanomedicine. Mater. Today 2015, 18, 12–19. [CrossRef] Keshavan, S.; Calligari, P.; Stella, L.; Fusco, L.; Delogu, L.G.; Fadeel, B. Nano-bio interactions: A neutrophil-centric view. Cell Death Dis. 2019, 10, 569. [CrossRef] Chen, M.; Qin, X.; Zeng, G. Biodegradation of carbon nanotubes, graphene, and their derivatives. Trends Biotechnol. 2017, 35, 836–846. [CrossRef] Gupta, N.; Rai, D.B.; Jangid, A.K.; Kulhari, H. A Review of theranostics applications and toxicities of carbon nanomaterials. Curr. Drug Metab. 2019, 20, 506–532. [CrossRef] Madannejad, R.; Shoaie, N.; Jahanpeyma, F.; Darvishi, M.H.; Azimzadeh, M.; Javadi, H. Toxicity of carbon-based nanomaterials: Reviewing recent reports in medical and biological systems. Chem. Biol. Interact. 2019, 307, 206–222. [CrossRef] Yuan, X.; Zhang, X.; Sun, L.; Wei, Y.; Wei, X. Cellular toxicity and immunological effects of carbon-based nanomaterials. Part. Fibre Toxicol. 2019, 16, 18. [CrossRef] Marchesan, S.; Melchionna, M.; Prato, M. Carbon Nanostructures for nanomedicine: Opportunities and challenges. Fuller. Nanotub. Carbon Nanostruct. 2014, 22, 190–195. [CrossRef] Rao, R.; Pint, C.L.; Islam, A.E.; Weatherup, R.S.; Hofmann, S.; Meshot, E.R.; Wu, F.; Zhou, C.; Dee, N.; Amama, P.B.; et al. Carbon nanotubes and related nanomaterials: Critical advances and challenges for synthesis toward mainstream commercial applications. ACS Nano 2018, 12, 11756–11784. [CrossRef] Iravani, S.; Varma, R.S. Green synthesis, biomedical and biotechnological applications of carbon and graphene quantum dots. A review. Environ. Chem. Lett. 2020, 1–25. [CrossRef] Caglayan, M.O.; Mindivan, F.; Şahin, S. Sensor and bioimaging studies based on carbon quantum dots: The green chemistry approach. Crit. Rev. Anal. Chem. 2020, 1–34. [CrossRef] Elessawy, N.A.; El-Sayed, E.M.; Ali, S.; Elkady, M.F.; Elnouby, M.; Hamad, H.A. One-pot green synthesis of magnetic fullerene nanocomposite for adsorption characteristics. J. Water Process Eng. 2020, 34, 101047. [CrossRef] Ahmed, G.H.; Laíño, R.B.; Calzón, J.A.; García, M.E. Facile synthesis of water-soluble carbon nano-onions under alkaline conditions. Beilstein J. Nanotechnol. 2016, 7, 758–766. [CrossRef] [PubMed] Sang, S.; Yang, S.; Guo, A.; Gao, X.; Wang, Y.; Zhang, C.; Cui, F.; Yang, X. Hydrothermal synthesis of carbon nano-onions from citric acid. Chem. Asian J. 2020, 15, 3428–3431. [CrossRef] Wei, X.; Li, L.; Liu, J.; Yu, L.; Li, H.; Cheng, F.; Yi, X.; He, J.; Li, B. Green synthesis of fluorescent carbon dots from gynostemma for bioimaging and antioxidant in zebrafish. ACS Appl. Mater. Interfaces 2019, 11, 9832–9840. [CrossRef] [PubMed] De Menezes, F.D.; Dos Reis, S.R.R.; Pinto, S.R.; Portilho, F.L.; do Vale Chaves, E.M.F.; Helal-Neto, E.; da Silva de Barros, A.O.; Alencar, L.M.R.; de Menezes, A.S.; Dos Santos, C.C.; et al. Graphene quantum dots unraveling: Green synthesis, characterization, radiolabeling with 99mTc, in vivo behavior and mutagenicity. Mater. Sci. Eng. C 2019, 102, 405–414. [CrossRef] Jovanović, S.P.; Syrgiannis, Z.; Budimir, M.D.; Milivojević, D.D.; Jovanovic, D.J.; Pavlović, V.B.; Papan, J.M.; Bartenwerfer, M.; Mojsin, M.M.; Stevanović, M.J.; et al. Graphene quantum dots as singlet oxygen producer or radical quencher-The matter of functionalization with urea/thiourea. Mater. Sci. Eng. C 2020, 109, 110539. [CrossRef] [PubMed] Chen, Y.; Zhao, C.; Wang, Y.; Rao, H.; Lu, Z.; Lu, C.; Shan, Z.; Ren, B.; Wu, W.; Wang, X. Green and high-yield synthesis of carbon dots for ratiometric fluorescent determination of pH and enzyme reactions. Mater. Sci. Eng. C 2020, 117, 111264. [CrossRef] Xu, L.; Li, Y.; Gao, S.; Niu, Y.; Liu, H.; Mei, C.; Cai, J.; Xu, C. Preparation and properties of cyanobacteria-based carbon quantum dots/polyvinyl alcohol/nanocellulose composite. Polymers 2020, 12, 1143. [CrossRef] Wang, Z.; Chen, D.; Gu, B.; Gao, B.; Wang, T.; Guo, Q.; Wang, G. Biomass-derived nitrogen doped graphene quantum dots with color-tunable emission for sensing, fluorescence ink and multicolor cell imaging. Spectrochim. Acta A 2020, 227, 117671. [CrossRef] [PubMed] Tadesse, A.; Hagos, M.; RamaDevi, D.; Basavaiah, K.; Belachew, N. Fluorescent-nitrogen-doped carbon quantum dots derived from citrus lemon juice: Green Synthesis, mercury(II) ion sensing, and live cell imaging. ACS Omega 2020, 5, 3889–3898. [CrossRef] [PubMed] Nair, S.S.P.; Kottam, N.; SG, P.K. Green Synthesized luminescent carbon nanodots for the sensing application of Fe3+ ions. J. Fluoresc. 2020, 30, 357–363. [CrossRef] [PubMed] Sahoo, N.K.; Jana, G.C.; Aktara, M.N.; Das, S.; Nayim, S.; Patra, A.; Bhattacharjee, P.; Bhadra, K.; Hossain, M. Carbon dots derived from lychee waste: Application for Fe3+ ions sensing in real water and multicolor cell imaging of skin melanoma cells. Mater. Sci. Eng. C 2020, 108, 110429. [CrossRef] Irmania, N.; Dehvari, K.; Gedda, G.; Tseng, P.J.; Chang, J.Y. Manganese-doped green tea-derived carbon quantum dots as a targeted dual imaging and photodynamic therapy platform. J. Biomed. Mater. Res. Part B Appl. Biomater. 2020, 108, 1616–1625. [CrossRef] [PubMed] Sharma, N.; Das, G.S.; Yun, K. Green synthesis of multipurpose carbon quantum dots from red cabbage and estimation of their antioxidant potential and bio-labeling activity. Appl. Microbiol. Biotechnol. 2020, 104, 7187–7200. [CrossRef] Appl. Sci. 2021, 11, 2490 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 15 of 20 Pandiyan, S.; Arumugam, L.; Srirengan, S.P.; Pitchan, R.; Sevugan, P.; Kannan, K.; Pitchan, G.; Hegde, T.A.; Gandhirajan, V. Biocompatible carbon quantum dots derived from sugarcane industrial wastes for effective nonlinear optical behavior and antimicrobial activity applications. ACS Omega 2020, 5, 30363–30372. [CrossRef] Liu, S.; Liu, Z.; Li, Q.; Xia, H.; Yang, W.; Wang, R.; Li, Y.; Zhao, H.; Tian, B. Facile synthesis of carbon dots from wheat straw for colorimetric and fluorescent detection of fluoride and cellular imaging. Spectrochim. Acta A 2021, 246, 118964. [CrossRef] Erdal, N.B.; Hakkarainen, M. Construction of bioactive and reinforced bioresorbable nanocomposites by reduced nano-graphene oxide carbon dots. Biomacromolecules 2018, 19, 1074–1081. [CrossRef] Başoğlu, A.; Ocak, Ü.; Gümrükçüoğlu, A. Synthesis of microwave-assisted fluorescence carbon quantum dots using roastedchickpeas and its applications for sensitive and selective detection of Fe3+ Ions. J. Fluoresc. 2020, 30, 515–526. [CrossRef] Qu, C.; Zhang, D.; Yang, R.; Hu, J.; Qu, L. Nitrogen and sulfur co-doped graphene quantum dots for the highly sensitive and selective detection of mercury ion in living cells. Spectrochim. Acta A 2019, 206, 588–596. [CrossRef] Zhang, M.; Cheng, J.; Zhang, Y.; Kong, H.; Wang, S.; Luo, J.; Qu, H.; Zhao, Y. Green synthesis of Zingiberis rhizoma-based carbon dots attenuates chemical and thermal stimulus pain in mice. Nanomedicine 2020, 15, 851–869. [CrossRef] Gudimella, K.K.; Appidi, T.; Wu, H.F.; Battula, V.; Jogdand, A.; Rengan, A.K.; Gedda, G. Sand bath assisted green synthesis of carbon dots from citrus fruit peels for free radical scavenging and cell imaging. Colloids Surf. B 2021, 197, 111362. [CrossRef] Li, C.; Sun, X.; Li, Y.; Liu, H.; Long, B.; Xie, D.; Chen, J.; Wang, K. Rapid and green fabrication of carbon dots for cellular imaging and anti-counterfeiting applications. ACS Omega 2021, 6, 3232–3237. [CrossRef] Xiao, J.; Liu, P.; Yang, G.W. Nanodiamonds from coal under ambient conditions. Nanoscale 2015, 7, 6114–6125. [CrossRef] Jirásek, V.; Stehlík, Š.; Štenclová, P.; Artemenko, A.; Rezek, B.; Kromka, A. Hydroxylation and self-assembly of colloidal hydrogenated nanodiamonds by aqueous oxygen radicals from atmospheric pressure plasma jet. RSC Adv. 2018, 8, 37681–37692. [CrossRef] Shi, Y.; Shi, Z.; Li, S.; Zhang, Y.; He, B.; Peng, D.; Tian, J.; Zhao, M.; Wang, X.; Zhang, Q. The interactions of single-wall carbon nanohorns with polar epithelium. Int. J. Nanomed. 2017, 12, 4177–4194. [CrossRef] Pei, S.; Wei, Q.; Huang, K.; Cheng, H.M.; Ren, W. Green synthesis of graphene oxide by seconds timescale water electrolytic oxidation. Nat. Commun. 2018, 9, 145. [CrossRef] Chen, D.; Lin, Z.; Sartin, M.M.; Huang, T.X.; Liu, J.; Zhang, Q.; Han, L.; Li, J.F.; Tian, Z.Q.; Zhan, D. Photosynergetic electrochemical synthesis of graphene oxide. J. Am. Chem. Soc. 2020, 142, 6516–6520. [CrossRef] [PubMed] Dasgupta, A.; Sarkar, J.; Ghosh, M.; Bhattacharya, A.; Mukherjee, A.; Chattopadhyay, D.; Acharya, K. Green conversion of graphene oxide to graphene nanosheets and its biosafety study. PLoS ONE 2017, 12, e0171607. [CrossRef] [PubMed] Ganguly, S.; Das, P.; Maity, P.P.; Mondal, S.; Ghosh, S.; Dhara, S.; Das, N.C. Green reduced graphene oxide toughened semi-IPN monolith hydrogel as dual responsive drug release system: Rheological, physicomechanical, and electrical evaluations. J. Phys. Chem. B 2018, 122, 7201–7218. [CrossRef] Cherian, R.S.; Sandeman, S.; Ray, S.; Savina, I.N.; Ashtami, J.; Mohanan, P.V. Green synthesis of Pluronic stabilized reduced graphene oxide: Chemical and biological characterization. Colloids Surf. B 2019, 179, 94–106. [CrossRef] Goodarzi, S.; Da Ros, T.; Conde, J.; Sefat, F.; Mozafari, M. Fullerene: Biomedical engineers get to revisit an old friend. Mater. Today 2017, 20, 460–480. [CrossRef] Kazemzadeh, H.; Mozafari, M. Fullerene-based delivery systems. Drug Discov. Today 2019, 24, 898–905. [CrossRef] [PubMed] Serda, M.; Szewczyk, G.; Krzysztyńska-Kuleta, O.; Korzuch, J.; Dulski, M.; Musioł, R.; Sarna, T. Developing [60] fullerene nanomaterials for better photodynamic treatment of non-melanoma skin cancers. ACS Biomater. Sci. Eng. 2020, 6, 5930–5940. [CrossRef] [PubMed] Akhtar, M.J.; Ahamed, M.; Alhadlaq, H.A.; Alshamsan, A. Mechanism of ROS scavenging and antioxidant signalling by redox metallic and fullerene nanomaterials: Potential implications in ROS associated degenerative disorders. Biochim. Biophys. Acta 2017, 1861, 802–813. [CrossRef] Galvan, Y.P.; Alperovich, I.; Zolotukhin, P.; Prazdnova, E.; Mazanko, M.; Belanova, A.; Chistyakov, V. Fullerenes as anti-aging antioxidants. Curr. Aging Sci. 2017, 10, 56–67. [CrossRef] [PubMed] Innocenzi, P.; Stagi, L. Carbon-based antiviral nanomaterials: Graphene, C-dots, and fullerenes. A perspective. Chem. Sci. 2020, 11, 6606–6622. [CrossRef] Hetzel, R.; Manning, T.; Lovingood, D.; Strouse, G.; Phillips, D. Production of Fullerenes by microwave synthesis. Fuller. Nanotub. Carbon Nanostruct. 2012, 20, 99–108. [CrossRef] Ramazani, A.; Moghaddasi, M.A.; Mashhadi Malekzadeh, A.; Rezayati, S.; Hanifehpour, Y.; Joo, S.W. Industrial oriented approach on fullerene preparation methods. Inorg. Chem. Commun. 2021, 125, 108442. [CrossRef] Zhang, X.; Ma, Y.; Fu, S.; Zhang, A. Facile synthesis of water-soluble fullerene (C60 ) nanoparticles via mussel-inspired chemistry as efficient antioxidants. Nanomaterials 2019, 9, 1647. [CrossRef] Afreen, S.; Zhu, J.J. Effect of switching ultrasonic amplitude in preparing a hybrid of fullerene (C60 ) and gallium oxide (Ga2 O3 ). Ultrason. Sonochem. 2020, 67, 105178. [CrossRef] Cumba, L.R.; Camisasca, A.; Giordani, S.; Forster, R.J. Electrochemical properties of screen-printed carbon nano-onion electrodes. Molecules 2020, 25, 3884. [CrossRef] Bartkowski, M.; Giordani, S. Carbon nano-onions as potential nanocarriers for drug delivery. Dalton Trans. 2021. [CrossRef] Appl. Sci. 2021, 11, 2490 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 16 of 20 D’Amora, M.; Rodio, M.; Bartelmess, J.; Sancataldo, G.; Brescia, R.; Cella Zanacchi, F.; Diaspro, A.; Giordani, S. Biocompatibility and biodistribution of functionalized carbon nano-onions (f-CNOs) in a vertebrate model. Sci. Rep. 2016, 6, 33923. [CrossRef] Trusel, M.; Baldrighi, M.; Marotta, R.; Gatto, F.; Pesce, M.; Frasconi, M.; Catelani, T.; Papaleo, F.; Pompa, P.P.; Tonini, R.; et al. Internalization of carbon nano-onions by hippocampal cells preserves neuronal circuit function and recognition memory. ACS Appl. Mater. Interfaces 2018, 10, 16952–16963. [CrossRef] [PubMed] Bowman, T.; Walter, A.; Shenderova, O.; Nunn, N.; McGuire, G.; El-Shenawee, M. A phantom study of terahertz spectroscopy and imaging of micro- and nano-diamonds and nano-onions as contrast agents for breast cancer. Biomed. Phys. Eng. Express 2017, 3, 055001. [CrossRef] Lettieri, S.; d’Amora, M.; Camisasca, A.; Diaspro, A.; Giordani, S. Carbon nano-onions as fluorescent on/off modulated nanoprobes for diagnostics. Beilstein J. Nanotechnol. 2017, 8, 1878–1888. [CrossRef] [PubMed] Grande Tovar, C.D.; Castro, J.I.; Valencia, C.H.; Navia Porras, D.P.; Mina Hernandez, J.H.; Valencia, M.E.; Velásquez, J.D.; Chaur, M.N. Preparation of chitosan/poly(vinyl alcohol) nanocomposite films incorporated with oxidized carbon nano-onions (multi-layer fullerenes) for tissue-engineering applications. Biomolecules 2019, 9, 684. [CrossRef] Mamidi, N.; Villela Castrejón, J.; González-Ortiz, A. Rational design and engineering of carbon nano-onions reinforced natural protein nanocomposite hydrogels for biomedical applications. J. Mech. Behav. Biomed. Mater. 2020, 104, 103696. [CrossRef] Kang, N.; Hua, J.; Gao, L.; Zhang, B.; Pang, J. The interplay between whey protein fibrils with carbon nanotubes or carbon nano-onions. Materials 2021, 14, 608. [CrossRef] D’Amora, M.; Camisasca, A.; Boarino, A.; Arpicco, S.; Giordani, S. Supramolecular functionalization of carbon nano-onions with hyaluronic acid-phospholipid conjugates for selective targeting of cancer cells. Colloids Surf. B 2020, 188, 110779. [CrossRef] [PubMed] Liang, T.; Liu, E.; Li, M.; Ushakova, E.V.; Kershaw, S.V.; Rogach, A.L.; Tang, Z.; Qu, S. Morphology control of luminescent carbon nanomaterials: From dots to rolls and belts. ACS Nano 2021, 15, 1579–1586. [CrossRef] [PubMed] Zhao, P.; Jin, B.; Zhang, Q.; Peng, R. High-quality carbon nitride quantum dots on photoluminescence: Effect of Carbon sources. Langmuir 2021, 37, 1760–1767. [CrossRef] Knoblauch, R.; Geddes, C.D. Carbon nanodots in photodynamic antimicrobial therapy: A review. Materials 2020, 13, 4004. [CrossRef] [PubMed] Saravanan, A.; Maruthapandi, M.; Das, P.; Luong, J.H.T.; Gedanken, A. Green synthesis of multifunctional carbon dots with antibacterial activities. Nanomaterials 2021, 11, 369. [CrossRef] Karimi, S.; Namazi, H. Simple preparation of maltose-functionalized dendrimer/graphene quantum dots as a pH-sensitive biocompatible carrier for targeted delivery of doxorubicin. Int. J. Biol. Macromol. 2020, 156, 648–659. [CrossRef] [PubMed] Guo, Z.; Li, Q.; Li, Z.; Liu, C.; Liu, X.; Liu, Y.; Dong, G.; Lan, T.; Wei, Y. Fabrication of efficient alginate composite beads embedded with N-doped carbon dots and their application for enhanced rare earth elements adsorption from aqueous solutions. J. Colloid Interface Sci. 2020, 562, 224–234. [CrossRef] Zhu, J.; Tang, Y.; Wang, G.; Mao, J.; Liu, Z.; Sun, T.; Wang, M.; Chen, D.; Yang, Y.; Li, J.; et al. Green, rapid, and universal preparation approach of graphene quantum dots under ultraviolet irradiation. ACS Appl. Mater. Interfaces 2017, 9, 14470–14477. [CrossRef] [PubMed] Kumawat, M.K.; Thakur, M.; Gurung, R.B.; Srivastava, R. Graphene quantum dots for cell proliferation, nucleus imaging, and photoluminescent sensing applications. Sci. Rep. 2017, 7, 15858. [CrossRef] [PubMed] Jiang, X.; Huang, J.; Chen, T.; Zhao, Q.; Xu, F.; Zhang, X. Synthesis of hemicellulose/deep eutectic solvent based carbon quantum dots for ultrasensitive detection of Ag+ and L-cysteine with “off-on” pattern. Int. J. Biol. Macromol. 2020, 153, 412–420. [CrossRef] Zhu, Z.; Yang, P.; Li, X.; Luo, M.; Zhang, W.; Chen, M.; Zhou, X. Green preparation of palm powder-derived carbon dots co-doped with sulfur/chlorine and their application in visible-light photocatalysis. Spectrochim. Acta A 2020, 227, 117659. [CrossRef] Shahid, S.; Mohiyuddin, S.; Packirisamy, G. Synthesis of multi-color fluorescent carbon dots from mint leaves: A robust bioimaging agent with potential antioxidant activity. J. Nanosci. Nanotechnol. 2020, 20, 6305–6316. [CrossRef] Roshni, V.; Gujar, V.; Muntjeeb, S.; Doshi, P.; Ottoor, D. Novel and reliable chemosensor based on C. dots from Sunflower seeds for the distinct detection of picric acid and bilirubin. Spectrochim. Acta A 2020, 250, 119354. [CrossRef] [PubMed] Wang, S.; Sun, W.; Yang, D.S.; Yang, F. Soybean-derived blue photoluminescent carbon dots. Beilstein J. Nanotechnol. 2020, 11, 606–619. [CrossRef] [PubMed] Shukla, D.; Das, M.; Kasade, D.; Pandey, M.; Dubey, A.K.; Yadav, S.K.; Parmar, A.S. Sandalwood-derived carbon quantum dots as bioimaging tools to investigate the toxicological effects of malachite green in model organisms. Chemosphere 2020, 248, 125998. [CrossRef] Cringoli, M.C.; Kralj, S.; Kurbasic, M.; Urban, M.; Marchesan, S. Luminescent supramolecular hydrogels from a tripeptide and nitrogen-doped carbon nanodots. Beilstein J. Nanotechnol. 2017, 8, 1553–1562. [CrossRef] [PubMed] Ansari, S.; Masoum, S. Recent advances and future trends on molecularly imprinted polymer-based fluorescence sensors with luminescent carbon dots. Talanta 2021, 223, 121411. [CrossRef] [PubMed] Kousheh, S.A.; Moradi, M.; Tajik, H.; Molaei, R. Preparation of antimicrobial/ultraviolet protective bacterial nanocellulose film with carbon dots synthesized from lactic acid bacteria. Int. J. Biol. Macromol. 2020, 155, 216–225. [CrossRef] Lin, Y.; Sun, X.; Su, D.S.; Centi, G.; Perathoner, S. Catalysis by hybrid sp2 /sp3 nanodiamonds and their role in the design of advanced nanocarbon materials. Chem. Soc. Rev. 2018, 47, 8438–8473. [CrossRef] [PubMed] Appl. Sci. 2021, 11, 2490 17 of 20 119. Reina, G.; Zhao, L.; Bianco, A.; Komatsu, N. Chemical functionalization of nanodiamonds: Opportunities and challenges ahead. Angew. Chem. Int. Ed. 2019, 58, 17918–17929. [CrossRef] [PubMed] 120. Jariwala, D.H.; Patel, D.; Wairkar, S. Surface functionalization of nanodiamonds for biomedical applications. Mater. Sci. Eng. C 2020, 113, 110996. [CrossRef] 121. Mochalin, V.N.; Gogotsi, Y. Nanodiamond–polymer composites. Diam. Relat. Mater. 2015, 58, 161–171. [CrossRef] 122. Yang, T.-C.; Chang, C.-Y.; Yarmishyn, A.A.; Mao, Y.-S.; Yang, Y.-P.; Wang, M.-L.; Hsu, C.-C.; Yang, H.-Y.; Hwang, D.-K.; Chen, S.-J.; et al. Carboxylated nanodiamond-mediated CRISPR-Cas9 delivery of human retinoschisis mutation into human iPSCs and mouse retina. Acta Biomater. 2020, 101, 484–494. [CrossRef] 123. Neburkova, J.; Vavra, J.; Cigler, P. Coating nanodiamonds with biocompatible shells for applications in biology and medicine. Curr. Opin. Solid State Mater. Sci. 2017, 21, 43–53. [CrossRef] 124. Madamsetty, V.S.; Pal, K.; Keshavan, S.; Caulfield, T.R.; Dutta, S.K.; Wang, E.; Fadeel, B.; Mukhopadhyay, D. Development of multi-drug loaded PEGylated nanodiamonds to inhibit tumor growth and metastasis in genetically engineered mouse models of pancreatic cancer. Nanoscale 2019, 11, 22006–22018. [CrossRef] [PubMed] 125. Garg, S.; Garg, A.; Sahu, N.K.; Yadav, A.K. Synthesis and characterization of nanodiamond-anticancer drug conjugates for tumor targeting. Diam. Relat. Mater. 2019, 94, 172–185. [CrossRef] 126. Cordina, N.M.; Sayyadi, N.; Parker, L.M.; Everest-Dass, A.; Brown, L.J.; Packer, N.H. Reduced background autofluorescence for cell imaging using nanodiamonds and lanthanide chelates. Sci. Rep. 2018, 8, 4521. [CrossRef] [PubMed] 127. Hsieh, F.-J.; Sotoma, S.; Lin, H.-H.; Cheng, C.-Y.; Yu, T.-Y.; Hsieh, C.-L.; Lin, C.-H.; Chang, H.-C. Bioorthogonal fluorescent nanodiamonds for continuous long-term imaging and tracking of membrane proteins. ACS Appl. Mater. Interfaces 2019, 11, 19774–19781. [CrossRef] [PubMed] 128. Barton, J.; Gulka, M.; Tarabek, J.; Mindarava, Y.; Wang, Z.; Schimer, J.; Raabova, H.; Bednar, J.; Plenio, M.B.; Jelezko, F.; et al. Nanoscale dynamic readout of a chemical redox process using radicals coupled with nitrogen-vacancy centers in nanodiamonds. ACS Nano 2020, 14, 12938–12950. [CrossRef] 129. Jung, H.-S.; Cho, K.-J.; Seol, Y.; Takagi, Y.; Dittmore, A.; Roche, P.A.; Neuman, K.C. Polydopamine encapsulation of fluorescent nanodiamonds for biomedical applications. Adv. Funct. Mater. 2018, 28, 1801252. [CrossRef] 130. Zhang, T.; Liu, G.-Q.; Leong, W.-H.; Liu, C.-F.; Kwok, M.-H.; Ngai, T.; Liu, R.-B.; Li, Q. Hybrid nanodiamond quantum sensors enabled by volume phase transitions of hydrogels. Nat. Commun. 2018, 9, 3188. [CrossRef] 131. Moore, L.K.; Caldwell, M.A.; Townsend, T.R.; MacRenaris, K.W.; Moyle-Heyrman, G.; Rammohan, N.; Schonher, E.K.; Burdette, J.E.; Ho, D.; Meade, T.J. Water-soluble nanoconjugate for enhanced cellular delivery of receptor-targeted magnetic resonance contrast agents. Bioconj. Chem. 2019, 30, 2947–2957. [CrossRef] [PubMed] 132. Szunerits, S.; Barras, A.; Boukherroub, R. Antibacterial applications of nanodiamonds. Int. J. Environ. Res. Public Health 2016, 13, 413. [CrossRef] [PubMed] 133. Torres Sangiao, E.; Holban, A.M.; Gestal, M.C. Applications of nanodiamonds in the detection and therapy of infectious diseases. Materials 2019, 12, 1639. [CrossRef] [PubMed] 134. Whitlow, J.; Pacelli, S.; Paul, A. Multifunctional nanodiamonds in regenerative medicine: Recent advances and future directions. J. Control. Release 2017, 261, 62–86. [CrossRef] 135. Barnard, A.S. Predicting the impact of structural diversity on the performance of nanodiamond drug carriers. Nanoscale 2018, 10, 8893–8910. [CrossRef] [PubMed] 136. Chipaux, M.; van der Laan, K.J.; Hemelaar, S.R.; Hasani, M.; Zheng, T.; Schirhagl, R. Nanodiamonds and their applications in cells. Small 2018, 14, e1704263. [CrossRef] 137. Namdar, R.; Nafisi, S. Nanodiamond applications in skin preparations. Drug Discov. Today 2018, 23, 1152–1158. [CrossRef] 138. Van der Laan, K.; Hasani, M.; Zheng, T.; Schirhagl, R. Nanodiamonds for in vivo applications. Small 2018, 14, e1703838. [CrossRef] [PubMed] 139. Torelli, M.D.; Nunn, N.A.; Shenderova, O.A. A perspective on fluorescent nanodiamond bioimaging. Small 2019, 15, e1902151. [CrossRef] 140. Cui, Z.; Zhang, Y.; Xia, K.; Yan, Q.; Kong, H.; Zhang, J.; Zuo, X.; Shi, J.; Wang, L.; Zhu, Y.; et al. Nanodiamond autophagy inhibitor allosterically improves the arsenical-based therapy of solid tumors. Nat. Commun. 2018, 9, 4347. [CrossRef] 141. Ali, M.S.; Metwally, A.A.; Fahmy, R.H.; Osman, R. Nanodiamonds: Minuscule gems that ferry antineoplastic drugs to resistant tumors. Int. J. Pharm. 2019, 558, 165–176. [CrossRef] [PubMed] 142. Gao, G.; Guo, Q.; Zhi, J. Nanodiamond-based theranostic platform for drug delivery and bioimaging. Small 2019, 15, e1902238. [CrossRef] 143. Tinwala, H.; Wairkar, S. Production, surface modification and biomedical applications of nanodiamonds: A sparkling tool for theranostics. Mater. Sci. Eng. C 2019, 97, 913–931. [CrossRef] [PubMed] 144. Miller, B.S.; Bezinge, L.; Gliddon, H.D.; Huang, D.; Dold, G.; Gray, E.R.; Heaney, J.; Dobson, P.J.; Nastouli, E.; Morton, J.J. Spin-enhanced nanodiamond biosensing for ultrasensitive diagnostics. Nature 2020, 587, 588–593. [CrossRef] [PubMed] 145. Karami, P.; Salkhi Khasraghi, S.; Hashemi, M.; Rabiei, S.; Shojaei, A. Polymer/nanodiamond composites-a comprehensive review from synthesis and fabrication to properties and applications. Adv. Colloid Interface Sci. 2019, 269, 122–151. [CrossRef] [PubMed] 146. Shvidchenko, A.V.; Eidelman, E.D.; Vul, A.Y.; Kuznetsov, N.M.; Stolyarova, D.Y.; Belousov, S.I.; Chvalun, S.N. Colloids of detonation nanodiamond particles for advanced applications. Adv. Colloid Interface Sci. 2019, 268, 64–81. [CrossRef] [PubMed] Appl. Sci. 2021, 11, 2490 18 of 20 147. Saraf, J.; Kalia, K.; Bhattacharya, P.; Tekade, R.K. Growing synergy of nanodiamonds in neurodegenerative interventions. Drug Discov. Today 2019, 24, 584–594. [CrossRef] [PubMed] 148. Fusco, L.; Avitabile, E.; Armuzza, V.; Orecchioni, M.; Istif, A.; Bedognetti, D.; Da Ros, T.; Delogu, L.G. Impact of the surface functionalization on nanodiamond biocompatibility: A comprehensive view on human blood immune cells. Carbon 2020, 160, 390–404. [CrossRef] 149. Ali, H. Using Low Temperature, cost-effective and green methods to carbon nanohorn synthesis. Nanosci. Nanotechnol. Asia 2019, 9, 157–160. [CrossRef] 150. Moreno-Lanceta, A.; Medrano-Bosch, M.; Melgar-Lesmes, P. Single-walled carbon nanohorns as promising nanotube-derived delivery systems to treat cancer. Pharmaceutics 2020, 12, 850. [CrossRef] [PubMed] 151. Liu, X.; Ying, Y.; Ping, J. Structure, synthesis, and sensing applications of single-walled carbon nanohorns. Biosens. Bioelectron. 2020, 167, 112495. [CrossRef] 152. Shen, F.; Zhang, C.; Cai, Z.; Wang, J.; Zhang, X.; Machuki, J.O.; Shi, H.; Gao, F. Carbon Nanohorns/Pt nanoparticles/DNA nanoplatform for intracellular Zn2+ imaging and enhanced cooperative phototherapy of cancer cells. Anal. Chem. 2020, 92, 16158–16169. [CrossRef] [PubMed] 153. Piovesana, S.; Iglesias, D.; Melle-Franco, M.; Kralj, S.; Cavaliere, C.; Melchionna, M.; Laganà, A.; Capriotti, A.L.; Marchesan, S. Carbon nanostructure morphology templates nanocomposites for phosphoproteomics. Nano Res. 2020, 13, 380–388. [CrossRef] 154. Nakamura, M.; Ueda, K.; Yamamoto, Y.; Aoki, K.; Zhang, M.; Saito, N.; Yudasaka, M. Ibandronate-loaded carbon nanohorns fabricated using calcium phosphates as mediators and their effects on macrophages and osteoclasts. ACS Appl. Mater. Interfaces 2021, 13, 3701–3712. [CrossRef] 155. Paneer Selvam, K.; Nagahata, T.; Kato, K.; Koreishi, M.; Nakamura, T.; Nakamura, Y.; Nishikawa, T.; Satoh, A.; Hayashi, Y. Synthesis and characterization of conductive flexible cellulose carbon nanohorn sheets for human tissue applications. Biomater. Res. 2020, 24, 18. [CrossRef] 156. Hirata, E.; Miyako, E.; Hanagata, N.; Ushijima, N.; Sakaguchi, N.; Russier, J.; Yudasaka, M.; Iijima, S.; Bianco, A.; Yokoyama, A. Carbon nanohorns allow acceleration of osteoblast differentiation via macrophage activation. Nanoscale 2016, 8, 14514–14522. [CrossRef] 157. Shi, Y.; Peng, D.; Wang, D.; Zhao, Z.; Chen, B.; He, B.; Zhu, Y.; Wang, K.; Tian, J.; Zhang, Q. Biodistribution survey of oxidized single-wall carbon nanohorns following different administration routes by using label-free multispectral optoacoustic tomography. Int. J. Nanomed. 2019, 14, 9809–9821. [CrossRef] 158. Agresti, F.; Barison, S.; Famengo, A.; Pagura, C.; Fedele, L.; Rossi, S.; Bobbo, S.; Rancan, M.; Fabrizio, M. Surface oxidation of single wall carbon nanohorns for the production of surfactant free water-based colloids. J. Colloid Interface Sci. 2018, 514, 528–533. [CrossRef] [PubMed] 159. Devereux, S.J.; Cheung, S.; Daly, H.C.; O’Shea, D.F.; Quinn, S.J. Multimodal microscopy distinguishes extracellular aggregation and cellular uptake of single-walled carbon nanohorns. Chem. Eur. J. 2018, 24, 14162–14170. [CrossRef] 160. Iglesias, D.; Guerra, J.; Lucío, M.I.; González-Cano, R.C.; López Navarrete, J.T.; Ruiz Delgado, M.C.; Vázquez, E.; Herrero, M.A. Microwave-assisted functionalization of carbon nanohorns with oligothiophene units with SERS activity. Chem. Commun. 2020, 56, 8948–8951. [CrossRef] [PubMed] 161. Gao, C.; Dong, P.; Lin, Z.; Guo, X.; Jiang, B.P.; Ji, S.; Liang, H.; Shen, X.C. Near-infrared light responsive imaging-guided photothermal and photodynamic synergistic therapy nanoplatform based on carbon nanohorns for efficient cancer treatment. Chem. Eur. J. 2018, 24, 12827–12837. [CrossRef] 162. Gao, C.; Jian, J.; Lin, Z.; Yu, Y.X.; Jiang, B.P.; Chen, H.; Shen, X.C. Hypericin-loaded carbon nanohorn hybrid for combined photodynamic and photothermal therapy in vivo. Langmuir 2019, 35, 8228–8237. [CrossRef] [PubMed] 163. He, B.; Shi, Y.; Liang, Y.; Yang, A.; Fan, Z.; Yuan, L.; Zou, X.; Chang, X.; Zhang, H.; Wang, X.; et al. Single-walled carbonnanohorns improve biocompatibility over nanotubes by triggering less protein-initiated pyroptosis and apoptosis in macrophages. Nat. Commun. 2018, 9, 2393. [CrossRef] [PubMed] 164. Iglesias, D.; Melle-Franco, M.; Kurbasic, M.; Melchionna, M.; Abrami, M.; Grassi, M.; Prato, M.; Marchesan, S. Oxidized Nanocarbons-tripeptide supramolecular hydrogels: Shape matters! ACS Nano 2018, 12, 5530–5538. [CrossRef] 165. Ekwueme, E.C.; Rao, R.; Mohiuddin, M.; Pellegrini, M.; Lee, Y.S.; Reiter, M.P.; Jackson, J.; Freeman, J.W. Single-walled carbon nanohorns modulate tenocyte cellular response and tendon biomechanics. J. Biomed. Mater. Res. Part B Appl. Biomater. 2020, 108, 1907–1914. [CrossRef] [PubMed] 166. Hansen, S.F.; Lennquist, A. Carbon nanotubes added to the SIN List as a nanomaterial of very high concern. Nat. Nanotechnol. 2020, 15, 3–4. [CrossRef] 167. Fadeel, B.; Kostarelos, K. Grouping all carbon nanotubes into a single substance category is scientifically unjustified. Nat. Nanotechnol. 2020, 15, 164. [CrossRef] [PubMed] 168. Heller, D.A.; Jena, P.V.; Pasquali, M.; Kostarelos, K.; Delogu, L.G.; Meidl, R.E.; Rotkin, S.V.; Scheinberg, D.A.; Schwartz, R.E.; Terrones, M.; et al. Banning carbon nanotubes would be scientifically unjustified and damaging to innovation. Nat. Nanotechnol. 2020, 15, 164–166. [CrossRef] 169. Aoki, K.; Saito, N. Biocompatibility and carcinogenicity of carbon nanotubes as biomaterials. Nanomaterials 2020, 10, 264. [CrossRef] [PubMed] Appl. Sci. 2021, 11, 2490 19 of 20 170. Paez-Mayorga, J.; Hernández-Vargas, G.; Ruiz-Esparza, G.U.; Iqbal, H.M.N.; Wang, X.; Zhang, Y.S.; Parra-Saldivar, R.; Khademhosseini, A. Bioreactors for cardiac tissue engineering. Adv. Healthc. Mater. 2019, 8, e1701504. [CrossRef] 171. Aoki, K.; Ogihara, N.; Tanaka, M.; Haniu, H.; Saito, N. Carbon nanotube-based biomaterials for orthopaedic applications. J. Mater. Chem. B 2020, 8, 9227–9238. [CrossRef] [PubMed] 172. Mori, H.; Ogura, Y.; Enomoto, K.; Hara, M.; Maurstad, G.; Stokke, B.T.; Kitamura, S. Dense carbon-nanotube coating scaffolds stimulate osteogenic differentiation of mesenchymal stem cells. PLoS ONE 2020, 15, e0225589. [CrossRef] 173. Lekshmi, G.; Sana, S.S.; Nguyen, V.H.; Nguyen, T.H.C.; Nguyen, C.C.; Le, Q.V.; Peng, W. Recent progress in carbon nanotube polymer composites in tissue engineering and regeneration. Int. J. Mol. Sci. 2020, 21, 6440. [CrossRef] 174. Teixeira-Santos, R.; Gomes, M.; Gomes, L.C.; Mergulhão, F.J. Antimicrobial and anti-adhesive properties of carbon nanotube-based surfaces for medical applications: A systematic review. iScience 2021, 24, 102001. [CrossRef] [PubMed] 175. Anaya-Plaza, E.; Shaukat, A.; Lehtonen, I.; Kostiainen, M.A. Biomolecule-directed carbon nanotube self-assembly. Adv. Healthc. Mater. 2021, 10, e2001162. [CrossRef] [PubMed] 176. Deshmukh, M.A.; Jeon, J.Y.; Ha, T.J. Carbon nanotubes: An effective platform for biomedical electronics. Biosens. Bioelectron. 2020, 150, 111919. [CrossRef] [PubMed] 177. Wang, H.; Li, P.; Yu, D.; Zhang, Y.; Wang, Z.; Liu, C.; Qiu, H.; Liu, Z.; Ren, J.; Qu, X. Unraveling the enzymatic activity of oxygenated carbon nanotubes and their application in the treatment of bacterial infections. Nano Lett. 2018, 18, 3344–3351. [CrossRef] 178. Dutt, T.S.; Saxena, R.K. Enhanced antibody response to ovalbumin coupled to poly-dispersed acid functionalized single walled carbon nanotubes. Immunol. Lett. 2020, 217, 77–83. [CrossRef] [PubMed] 179. Iglesias, D.; Senokos, E.; Alemán, B.; Cabana, L.; Navío, C.; Marcilla, R.; Prato, M.; Vilatela, J.J.; Marchesan, S. Gas-phase functionalization of macroscopic carbon nanotube fiber assemblies: Reaction control, electrochemical properties, and use for flexible supercapacitors. ACS Appl. Mater. Interfaces 2018, 10, 5760–5770. [CrossRef] 180. Anju, V.T.; Paramanantham, P.; Siddhardha, B.; Sruthil Lal, S.B.; Sharan, A.; Alyousef, A.A.; Arshad, M.; Syed, A. Malachite green-conjugated multi-walled carbon nanotubes potentiate antimicrobial photodynamic inactivation of planktonic cells and biofilms of Pseudomonas aeruginosa and Staphylococcus aureus. Int. J. Nanomed. 2019, 14, 3861–3874. [CrossRef] 181. Almeida, T.C.S.; Martins-Júnior, P.A.; Joviano-Santos, J.V.; Andrade, V.B.; Ladeira, L.C.D.; Vieira, M.A.R.; Corrêa Junior, A.; Caliari, M.V.; Ladeira, L.O.; Ferreira, A.J. Carbon nanotubes functionalized with sodium hyaluronate: Sterilization, osteogenic capacity and renal function analysis. Life Sci. 2020, 248, 117460. [CrossRef] 182. Chudoba, D.; Łudzik, K.; Jażdżewska, M.; Wołoszczuk, S. Kinetic and equilibrium studies of doxorubicin adsorption onto carbon nanotubes. Int. J. Mol. Sci. 2020, 21, 8230. [CrossRef] [PubMed] 183. Yaghoubi, A.; Ramazani, A. Anticancer DOX delivery system based on CNTs: Functionalization, targeting and novel technologies. J. Control. Release 2020, 327, 198–224. [CrossRef] [PubMed] 184. Liu, L.; Yang, B.; Wang, L.Q.; Huang, J.P.; Chen, W.Y.; Ban, Q.; Zhang, Y.; You, R.; Yin, L.; Guan, Y.Q. Biomimetic bone tissue engineering hydrogel scaffolds constructed using ordered CNTs and HA induce the proliferation and differentiation of BMSCs. J. Mater. Chem. B 2020, 8, 558–567. [CrossRef] [PubMed] 185. Mao, Z.; Zhang, Y.; Lu, N.; Cheng, S.; Hong, R.; Liu, Q.H. Carbon nanotubes enabling highly efficient cell apoptosis by low-intensity nanosecond electric pulses via perturbing calcium handling. Small 2020, 16, e1904047. [CrossRef] 186. Edwards, C.H.; Christie, C.R.; Masotti, A.; Celluzzi, A.; Caporali, A.; Campbell, E.M. Dendrimer-coated carbon nanotubes deliver dsRNA and increase the efficacy of gene knockdown in the red flour beetle Tribolium castaneum. Sci. Rep. 2020, 10, 12422. [CrossRef] 187. Galassi, T.V.; Antman-Passig, M.; Yaari, Z.; Jessurun, J.; Schwartz, R.E.; Heller, D.A. Long-term in vivo biocompatibility of single-walled carbon nanotubes. PLoS ONE 2020, 15, e0226791. [CrossRef] 188. Hu, Y.; Niemeyer, C.M. Designer DNA-silica/carbon nanotube nanocomposites for traceable and targeted drug delivery. J. Mater. Chem. B 2020, 8, 2250–2255. [CrossRef] 189. Ravanbakhsh, H.; Bao, G.; Mongeau, L. Carbon nanotubes promote cell migration in hydrogels. Sci. Rep. 2020, 10, 2543. [CrossRef] 190. Shayganpour, A.; Nazarizadeh, S.; Grasselli, S.; Malchiodi, A.; Bayer, I.S. Stacked-cup carbon nanotube flexible paper based on soy lecithin and natural rubber. Nanomaterials 2019, 9, 824. [CrossRef] 191. Wick, P.; Louw-Gaume, A.E.; Kucki, M.; Krug, H.F.; Kostarelos, K.; Fadeel, B.; Dawson, K.A.; Salvati, A.; Vazquez, E.; Ballerini, L.; et al. Classification framework for graphene-based materials. Angew. Chem. Int. Ed. 2014, 53, 7714–7718. [CrossRef] [PubMed] 192. Reina, G.; González-Domínguez, J.M.; Criado, A.; Vázquez, E.; Bianco, A.; Prato, M. Promises, facts and challenges for graphene in biomedical applications. Chem. Soc. Rev. 2017, 46, 4400–4416. [CrossRef] [PubMed] 193. Ji, H.; Sun, H.; Qu, X. Antibacterial applications of graphene-based nanomaterials: Recent achievements and challenges. Adv. Drug Deliv. Rev. 2016, 105, 176–189. [CrossRef] [PubMed] 194. Rezapour, M.R.; Myung, C.W.; Yun, J.; Ghassami, A.; Li, N.; Yu, S.U.; Hajibabaei, A.; Park, Y.; Kim, K.S. Graphene and graphene analogs toward optical, electronic, spintronic, green-chemical, energy-material, sensing, and medical applications. ACS Appl. Mater. Interfaces 2017, 9, 24393–24406. [CrossRef] 195. You, X.; Yang, S.; Li, J.; Deng, Y.; Dai, L.; Peng, X.; Huang, H.; Sun, J.; Wang, G.; He, P.; et al. Green and mild oxidation: An efficient strategy toward water-dispersible graphene. ACS Appl. Mater. Interfaces 2017, 9, 2856–2866. [CrossRef] Appl. Sci. 2021, 11, 2490 20 of 20 196. Joshi, S.; Siddiqui, R.; Sharma, P.; Kumar, R.; Verma, G.; Saini, A. Green synthesis of peptide functionalized reduced graphene oxide (rGO) nano bioconjugate with enhanced antibacterial activity. Sci. Rep. 2020, 10, 9441. [CrossRef] 197. Ahmed, A.; Adak, B.; Bansala, T.; Mukhopadhyay, S. Green solvent processed cellulose/graphene oxide nanocomposite films with superior mechanical, thermal, and ultraviolet shielding properties. ACS Appl. Mater. Interfaces 2020, 12, 1687–1697. [CrossRef]