Processing of Chinese Material Medica (CMM) is a pharmaceutical technology to fulfill the different therapeutic requirements, dispensing and making preparations based on the theory of traditional Chinese medicine (Zhao et al., 2010). History of processing on charcoal drugs is summarized in Table 1 (Zhao et al., 2010; Jia et al., 2020; Sun et al., 2020). Chemical changes of Typha angustifolia L. [Typhaceae] in charring process were performed by UPLC and UPLC-MS analysis. It was found that a significant decrease in most flavonoid glycosides, and an increase in some flavonoid (e.g., isorhamnetin, quercetin, and kaempferol), or compounds, such as huaicarbon A/B, might occur (Chen et al., 2015). Undoubtedly, those newly yielded compounds are associated with the enhanced hemostatic activity. And components with increasing contents, for example, flavonoid aglycones and organic acids are also probably related to the enhancement of hemostasis (Gao et al., 2021). Like carbonized Typha angustifolia L. Nelumbo nucifera Gaertn. [Nelumbonaceae] also enhances hemostatic effect by carbonization. Researchers determined the flavonoid aglycones and flavonoid glycosides contents. The ethyl acetate extracts (flavonoid glycosides, 140.61 ± 5.26 mg/g; flavonoid aglycones, 62.26 ± 2.40 mg/g) could significantly reduce blood clotting time (Chen et al., 2020). Tannins (Cao et al., 2010), total flavonoids (Zhang et al., 2005) and CDs (Zhang et al., 2018) are active fractions with hemostasis in Nepeta tenuifolia Benth. [Lamiaceae]. Using charcoal drugs for the treatment of diseases is an interesting option and has been increasingly used in recent years. However, there are problems using charcoal drugs. By carbonizing, big changes of properties and effects of TCM might occur, However, the change paths of chemical constituents are unknown. So far, there is no generally accepted conclusion on the material basis of pharmacodynamics of charcoal drugs (Chen et al., 2019). Researchers have tried to elucidate the small molecule active compounds for the effects of charcoal drugs, and the results have been inconclusive. This situation has promoted studies on CDs generated in the charcoal processing (Luo et al., 2018).

Nanomedicine has made a considerable influence on the treatment of diseases (Min et al., 2015). CDs can be normally defined as a quasi-0D carbon-based nanomaterial with sizes below 20 nm, because of their diverse physicochemical characteristics and favorable attributes such as excellent biocompatibility, unique optical properties, lower cost, eco-friendliness, abundant functional groups (such as amino, hydroxyl, carboxyl), and high stability. CDs are widely applied in biomedical sciences, such as bio-imaging (e.g., in vivo and in vitro biological imaging), phototherapy (e.g., photodynamic and photothermal therapy), drug/gene delivery, and nanomedicine (Liu et al., 2020).

The charring process are intricate, involving chemistry, pharmacology, biochemistry, and others. Some scholars believed that high-temperature charring was the key to deriving a material basis for the effects of charcoal drugs (Chen et al., 2019). Methods involving CDs synthesis include electrochemical carbonization (Shinde and Pillai, 2013); microwave (Jaiswal et al., 2012); chemical ablation (Ray et al., 2009); laser ablation (Yang et al., 2009); water/solvent heat treatment; and high-temperature dissociation (Tang et al., 2019). The high-temperature dissociation is analogous to (high-temperature) carbonizing of carbon drugs (Chen et al., 2019).

Physicochemical properties and bioactivities of CDs derived from different charcoal medicines are different (Sun et al., 2018b). Previous studies found that CDs are the material basis for the activity of charcoal-processed drugs (Zhao et al., 2017; Sun et al., 2018b; Wang S. et al., 2019). Research on charcoal remedies in TCM has been centered on hemostasis, which is closely linked to the empirical theory of TCM. However, studies (other than those assessing effects on hemostasis) on charcoal-processed medicines are limited. Therefore, in the follow-up research, more emphasis should be placed on other applications (other than hemostasis) of carbon drugs. In 2014, Li, et al. obtained highly fluorescent and bioactive CDs prepared from Zingiber officinale Roscoe for the first time and found that the TCM-CDs effectively inhibited the growth of human hepatocellular (HepG2) cells (Li et al., 2014). Therefore, the properties of charcoal drugs can be explored by introducing CDs, mainly through introducing the characterization technology of the nanometer discipline and the classic models to assess the pharmacological activity of nano-drugs and the related mechanisms of action.

Despite the advantages of using CDs for clarifying the material basis of charcoal-processed drugs, there are some additional factors that need to be considered. With the current safety and bioactivities data of CDs, caution should be exercised, and the roles of CDs have yet to be adequately developed.

The aim of this article is to provide an overview of TCM-based CDs for the management of human diseases (including hemorrhagic diseases, gout, inflammatory diseases, cancer, pain of various forms and causes), discuss the intrinsic pharmacological activity of those CDs and their mechanisms of action to improve and promote their clinical application.

Use of TCM-based CDs is an interesting therapeutic approach for the treatment of hemorrhagic diseases and other commonly refractory diseases, including gout, inflammatory diseases, cancer, pain of various forms and causes. The possible role of CDs in different clinical settings is discussed below.

Uncontrolled bleeding in trauma patients remains a major challenge (Navarro and Brooks, 2015), not only in the field of surgery but also on battlefields. Trauma-induced hemorrhage leading to microcirculatory disorders and secondary inflammatory responses is related to multiple organ failure, resulting in increased mortality or morbidity (Hsu et al., 2012). Internal hemorrhage is a predominant cause of death after trauma on the battlefield (Gaharwar et al., 2014). There are many products available that use thrombin and fibrinogen to promote local hemostasis for intra-cavity hemorrhage (Navarro and Brooks, 2015). For instance, fibrin glue and tissue adhesive, are already commercialized to achieve hemostasis. Nevertheless, these approaches are not easy to employ on battlefields (Gaharwar et al., 2014). Hence, there is an imperative need to develop novel rational therapeutic strategies that can overcome these constraints in out-of-hospital, emergency circumstances (Cheng J. et al., 2019). Hemostasis by charcoal drugs played a significant role in TCM throughout history (Chen et al., 2019). Hemorrhage is a common complication of malignant tumors (Li et al., 2019). Sanguisorba officinalis L. [Rosaceae] Carbonisata can be used to treat hematochezia caused by liver cancer and gastric cancer (Yang et al., 2020). Modern medical researchers have proposed that the hemostatic properties of some herbs could be generated after carbonizing (Fang et al., 2011; Zhang et al., 2018). The activity study of CDs provides a novel avenue for exploring the effective substance basis employed in charcoal drugs and the role with an emphasis on specific charcoal drugs is discussed in the following paragraph.

Gout is a chronic disease resulting from the deposition of monosodium urate (MSU) crystals that form in the presence of elevated uric acid levels (Dalbeth et al., 2016). Clinical treatment of gout involves the sensible and prolonged reduction of plasma urate concentrations as well as inhibition of inflammatory response in acute gouty arthritis. Uric acid-lowering medications, such as xanthine oxidase (XOD) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and uricosuric agents, are commonly recommended for the treatment of gout, although long-term utilization of those drugs may cause side effects, such as myelosuppression, gastrointestinal irritation, and renal toxicity (Liang et al., 2019). Moreover, such drugs could not prevent, stop or reverse the advancement of this complicated diseases. Therefore, novel therapies or drugs intervention for the development of gout are urgently needed in clinic (Chi et al., 2020). The anti-gout activities of CDs derived from various natural products are yet to deserve further study in this setting.

Inflammation is the body’s immediate reaction to the tissues and cells that are damaged by pathogens, toxic stimuli including chemicals, or physical injury. The courses by which acute inflammatory disease is initiated and progresses are well defined, but much less is learned about the etiologies of chronic inflammation and the related molecular and cellular pathways. Chronic inflammation is long-term, dysregulated and maladaptive response that includes active inflammation, tissue destruction and an attempt at tissue repair. Such inflammation is relevant to many chronic human conditions and illnesses, including allergy, artery atherosclerosis, cancer, arthritis and autoimmune diseases (Weiss, 2008). Current therapy for inflammatory disorders is limited to both steroidal and non-steroidal anti-inflammatory drugs. The prolonged use of these agents frequently leads to severe adverse effects such as gastrointestinal, cardiovascular, and renal abnormalities. Therefore, there is a great demand to research new anti-inflammatory agents with selective effect and less toxicity (Patil et al., 2019). Studies focusing on CDs in Chinese herbal medicine is relatively scarce. The use of charcoal drugs has demonstrated promising results in treatment of diseases. The anti-inflammation activity of CDs derived from various herbs warrants further study.

Cancer remains a major threat to human health. Surgery, chemotherapy and drugs are the main treatments for cancer (Chen et al., 2021; Pei et al., 2021). In recent years, herbal medicine has drawn great attention in oncology because of its multi-targets, multi-pathways, and mild side effects (Chen et al., 2021). However, most active ingredients of herbal medicine are often characterized by poor water solubility, low biological availability and so on, which restrict their clinical applications (Li et al., 2020). CDs are low toxic and highly biological compatible, and are therefore considered much safer for the use of biology (Li et al., 2014). Previous studies have shown that CDs prepared from green tea have an inhibitory effect on human breast cancer (MDA-MB-231) cells growth, and are harmless to normal cells (Hsu et al., 2013). Nevertheless, much work remains to explore the cellular toxicity of the luminescent dots for broader biological applications (Li et al., 2014).

Management of pain of various types and causes, such as acute, chronic and cancer-related pain, is challenging in clinical practice (Podolsky et al., 2013). Cancer pain, acute or chronic pain have emerged as a Gordian knot in medical practice. Prescription opioids remain the first-line treatments for analgesia, but their misuse has escalated rapidly, resulting in a dramatic growth in cases of opioid reliance and overdose deaths (Brady et al., 2016; Liu et al., 2019), making it urgent to develop safer analgesic regimens involving nonopioid compounds. The pain relief effect of nanoparticles has gained attention. Limited information on the analgesic bioactivity of TCM-based CDs is available in this context.

Due to extensive developments in nanotechnology, the therapeutic efficacy of TCM-based CDs has been extensively studied. Moreover, many products are under different clinical trials.

The reports on the bioactivity and related mechanisms of CDs are uncommon, despite there is a growing interest in improving our comprehension on the interplay between nanomaterials and living systems (Yan et al., 2017). Despite this limitation, studies on classical animal models, pharmacological activity and related mechanisms of CDs for the treatment of diseases are discussed with regard to Cirsium arvense var. arvense [Asteraceae] (Luo et al., 2018), Phellodendron chinense C. K. Schneid. [Rutaceae] (Liu et al., 2018), Sesamum indicum L. [Pedaliaceae] (Sun et al., 2018a), Citrus × aurantium L. [Rutaceae] (Wang S. et al., 2019), Pueraria montana var. lobata (Willd.) Maesen and S.M.Almeida ex Sanjappa and Predeep [Fabaceae] (Wang X. et al., 2019), Lonicera japonica Thunb. [Caprifoliaceae] (Wu et al., 2020), Mulberry silkworm cocoon (MSC) (Wang et al., 2020), Zingiber officinale Roscoe [Zingiberaceae] (Li et al., 2014), Zingiber officinale Roscoe [Zingiberaceae] (Zhang et al., 2020), Typha angustifolia L. [Typhaceae] (Yan et al., 2017), Juncus effusus L. [Juncaceae] (Cheng J. et al., 2019), Sophora flavescens Aiton [Fabaceae] (Hu et al., 2021), Paeonia lactiflora Pall. [Paeoniaceae] (Zhao et al., 2020) and Phellodendron chinense C. K. Schneid. [Rutaceae] (Zhang et al., 2021). Based on this knowledge, a variety of herbs-derived CDs formulations were prepared, and these CDs derived from various natural products that exhibit different biological activities (other than hemostasis) are summarized in Table 2.

This paper reviews the biological activity of CDs derived from TCM and their possible mechanisms. The properties of TCM-CDs can be depicted as follows: 1) enhancing properties of raw products: Cirsium arvense var. arvense Carbonisata-CDs has stronger hemostatic effect than that of raw Cirsium arvense var. arvense; 2) generating new therapeutic efficacy: the biological activity of Phellodendron chinense C. K. Schneid. Carbonisata becomes hemostatic. Medicinal herb is chosen as the ideal choice of green precursors. Because herbal medicines as the natural products with high yield and approximately innocuousness. In addition, the unique diagnostic mode and therapy makes herbs significant in diseases treatment (Teschke et al., 2015; Li et al., 2017; Ma et al., 2019). More importantly, compared to western medicine, medicinal herbs are rich in active constitutes, thus have multiple pharmacodynamic substances (Li and Weng, 2017). Furthermore, compared to carbon drugs, a major advantage of CDs is easy to quantify, and the criteria is easily controlled.

Although green-CDs move steadily on the prospective path towards biomedicine, they cannot eliminate the shortcomings of drug loading (complicated manipulation and uncontrollable loading efficiency) (Radnia et al., 2020), and there are limitations of using charcoal drugs. There is no uniform objective quantitative indicator for processing carbon drugs. It is difficult to ensure the stable and uniform quality of charcoal products together with different CDs preparing conditions (temperature, time, et al.), which leads to possible differences in the structure of CDs derived from herbal medicines and uneven pharmacological activities.

A number of evidences show that CDs obtained from different precursors (Zhao et al., 2015; Atchudan et al., 2016) or preparation conditions (preparing temperature, time, et al.) (Sahu et al., 2012; Veltri et al., 2020) exhibited different properties, mainly in terms of size, charge, and chemical groups. The differences in these properties have been shown to be closely related to the bioactivities of CDs, which further offered a plausible explanation for the fact that different activities on CDs presently found (Zhang et al., 2021). Phellodendron chinense C. K. Schneid. Carbonisata-CDs prepared at 350°C exhibited remarkable hemostasis (Liu et al., 2018) and protection against acute kidney injury caused by D. acutus venom (Zhang et al., 2019), but there was no obvious efficacy of relieving psoriasis-skin inflammation. Better anti-psoriasis activity of Phellodendron chinense C. K. Schneid. Carbonisata-CDs obtained at 400°C have been demonstrated compared to CDs prepared at other temperature conditions (325°C and 475°C). Consequently, the mechanism correlated with structure-function relationship between TCM-CDs obtained at different preparation process and the corresponding bioactivity is still a challenge (Zhang et al., 2021). Additionally, whether all carbon points can be extracted from the charcoal drug needs further study.

Over the recent years, there are certain progresses of research on charcoal drugs. Subsequently research methods for charcoal medicine have also made remarkable progress. Zhong et al. (2016) evaluated the anti-inflammatory action of essential oil from processed products of Angelica sinensis (Oliv.) Diels [Apiaceae] by gas chromatography-mass spectrometry-based metabolomics. Cheng P. et al. (2019) revealed protective effect of Paeonia × suffruticosa Andrews [Paeoniaceae] charcoal on blood-heat and hemorrhage rats using 1 H nuclear magnetic resonance-based metabonomic.

Thus, to accelerate successful TCM-CDs translation from bench to besides and make it more valuable for clinical use. It’s necessary to establish a research platform that integrates the advantages of multiple disciplines. Nanomaterials, proteomics, genomics, metabolomics and other modern technologies should be introduced in promoting the studies on common processing mechanism of charcoal drugs and boosting the development of processing discipline (Gao et al., 2020). Systematic study on toxicity and metabolic pathways of TCM-CDs in animal models, other roles (other than hemostasis) of carbon drugs, for example, the Rheum palmatum L. [Polygonaceae]- and Rheum palmatum L- charcoal cause and stop diarrhea respectively, optimization of charcoal drug preparation method, the biodistribution and safety inspection of CDs coupled with the exact mechanism of interaction between living system and TCM-CDs that will be the emphasis of our future research.