Advancements in pharmaceutical research on traditional Chinese medicine-metal complexes

Abstract

Traditional Chinese medicine (TCM) has gained significant recognition as an adjuvant treatment modality for cancer, infections, and inflammatory diseases, owing to its outstanding antitumor, antimicrobial, and anti-inflammatory properties. With the advancement of TCM-based coordination chemistry, TCM-metal complexes have attracted growing interest in recent years. These novel compounds, formed by integrating traditional TCM components with metal ions, not only enhance the therapeutic efficacy of TCM but also exhibit unique biological activities. This review highlights the design strategies and pharmaceutical applications of various categories of TCM-metal complexes, including those based on polyphenols, alkaloids, and other drug-metal conjugates. By applying modern nanobiotechnology alongside TCM principles, TCM-metal complexes demonstrate considerable potential for the diagnosis and treatment of major diseases. Finally, this review discusses the challenges and future prospects of TCM-metal complexes in clinical applications, providing valuable insights to guide further research and development in this emerging field.

Graphical abstract

Highlights

• •Metal coordination enhances the therapeutic efficacy of TCM.
• •TCM-metal complexes exhibit diverse structures and bioactivities.
• •Nanobiotechnology improves delivery and targeting of these complexes.
• •Challenges remain in toxicity, biocompatibility, and clinical translation.

1. Introduction

1.1. Overview of traditional Chinese medicine (TCM)

TCM has played a vital role in disease prevention and treatment across Asia for thousands of years and remains a cornerstone of complementary and alternative therapy in China today [1]. The most widely used forms of TCM include Chinese herbal medicines (CHMs), which are composed by both herbal slices (HSs) and Chinese patent drugs (CPDs) [2]. Owing to its demonstrated efficacy and low incidence of side effects, TCM is increasingly employed to manage chronic and complex conditions. Notably, CHM has been shown to reduce toxicity, improve short-term treatment responses, and extend survival in patients with diseases such as non-small cell lung cancer (NSCLC) [[3], [4], [5], [6]].

Central to TCM's therapeutic value is a rich reservoir of bioactive phytochemicals. Many natural compounds derived from medicinal plants exhibit significant pharmacological effects relevant to modern drug development [[7], [8], [9]]. For instance, curcumin, resveratrol, quercetin, and tanshinone IIA have demonstrated antitumor activity by modulating multiple signaling pathways, inhibiting metastasis, and inducing apoptosis [10]. Beyond their anticancer effects, numerous TCM-derived compounds also possess anti-inflammatory and antimicrobial properties, contributing to their broad clinical applications. For example, baicalin mitigates inflammation through the inhibition of pro-inflammatory cytokines [11,12]. Similarly, tanshinone and salvianolic acid from Salvia miltiorrhiza exert anti-inflammatory and cardioprotective effects, making them useful in conditions like rheumatoid arthritis and cardiovascular disease [13,14]. Similarly, compounds from Lonicera japonica and Forsythia suspensa display antimicrobial activity against respiratory pathogens, and matrine from Sophora flavescens inhibits bacterial growth [15,16].

In addition to these traditional therapeutic uses, modern technologies such as high-throughput screening and pharmacological modeling have deepened our understanding of TCM's mechanisms of action. The most prominent example is artemisinin, derived from Artemisia annua, which revolutionized malaria treatment and earned a Nobel Prize [17]. TCM continues to be actively investigated for a wide range of conditions, including diabetes, cardiovascular disease, and neurological disorders [[18], [19], [20], [21], [22], [23]].

Rather than focusing on theoretical constructs such as yin-yang and five elements, modern TCM research increasingly emphasizes chemically defined bioactive compounds with therapeutic potential. These compounds, particularly polyphenols, alkaloids, polysaccharides, and saponins, are rich in donor atoms (e.g., hydroxyl, carboxyl, and amino groups), making them suitable for forming coordination complexes with metal ions. This provides the foundation for the emerging interdisciplinary field of TCM-metal complexes, which harnesses the synergy between traditional compounds and modern coordination chemistry for pharmaceutical innovation.

1.2. Overview of TCM-metal complexes

As TCM continues to evolve, accumulating evidence suggests that the pharmacological activity of certain TCM constituents may decline or even cause adverse effects after isolation and purification [24]. In response to this observation, the TCM coordination theory was proposed in 1993, which posits that the true active forms of TCM may be metal-ligand complexes formed in vivo or during traditional decoction [25]. Many bioactive TCM molecules contain functional groups such as carboxyl, sulfhydryl, and hydroxyl moieties capable of binding metal ions to form stable coordination complexes [24].

Building on this hypothesis, TCM-metal complexes have gained increasing attention as multi-functional therapeutic agents. Conjugation of metal ions to TCM ligands not only improves pharmacokinetic properties, including solubility and membrane permeability, but also enhances or even imparts new biological activities [24,26]. For instance, emodin, which exhibits weak intrinsic antitumor activity, shows significantly enhanced cytotoxicity against cancer cells when coordinated with metal ions [26,27]. Similarly, baicalin-metal complexes, particularly those with rare earth elements, exhibit superior antioxidant capacity and protect erythrocytes more effectively than baicalin alone [28,29].

This review aims to provide a comprehensive overview of TCM-metal complexes, including their classification, coordination chemistry, therapeutic applications, and mechanisms of action. Particular emphasis is placed on how the integration of TCM ligands with metal ions enhances pharmacological efficacy in areas such as oncology, infectious disease, and inflammation. The review concludes by addressing current challenges and outlining future directions for the clinical translation of TCM-metal complexes.

2. General classification of TCM-metal complexes

TCM-metal complexes are formed by integrating TCM components with metal ions or inorganic nanoparticles, which can significantly enhance drug efficacy through synergistic TCM-metal interactions. The incorporation of metal ions with active TCM ingredients not only improves the stability and bioavailability of the compounds but also amplifies their therapeutic effects. TCM-metal complexes can be broadly classified into the following categories: polyphenol-metal complexes, alkaloid-metal complexes, polysaccharide-metal complexes, and saponin-metal complexes (Scheme 1).

Scheme 1.

General classification of traditional Chinese medicine (TCM)-metal complexes.

2.1. Polyphenol-metal complexes

Polyphenols, naturally occurring metabolites predominantly found in plants, are diverse compounds that include non-flavonoids (such as curcuminoids, phenolic acids, and stilbenes) [30] (Figs. 1A–C) and flavonoids (including tea polyphenols, flavanones, flavonols, flavones, and flavanonols) [30] (Fig. 1D). These polyphenols exhibit a wide range of biopharmacological activities, including antioxidant, anti-inflammatory, anti-fibrotic, and antitumor effects. They are also characterized by low systemic toxicity and favorable metabolism in the human body, making them highly promising candidates for clinical applications [31,32]. The polyphenol structure typically consists of two or more phenolic hydroxyl groups connected by stable C−C or ester bonds. Due to the presence of phenolic hydroxyl groups and aromatic rings, polyphenols can form complexes with various metal ions through covalent interactions such as Michael addition, Schiff-base reactions, and coordination bonds [33].

Fig. 1.

Chemical structures of different polyphenol classes. (A) Curcumin, exhibiting typical keto-enol tautomerism. (B) Phenolic acids. (C) Stilbenes. (D) Typical carbon skeleton of flavonoids, all flavonoids share a common three-ring carbon skeleton. (E) Zn-curcumin. (F) Zn-quercetin. (G) Representative flavonoid structures found in Ginkgo biloba.

Curcumin is a hydrophobic polyphenolic compound isolated from turmeric, which exhibits keto-enol tautomerism. In alkaline media, it predominantly exists in the stable enol form, while in acidic and neutral solutions, it adopts the ketone form [30] (Fig. 1A). Curcumin has been shown to possess a wide range of pharmacological activities, including antioxidant, anti-inflammatory, antibacterial, hypoglycemic, and anti-rheumatic effects [34,35]. It plays an adjuvant role in the treatment of various chronic diseases, such as liver disease, cardiovascular conditions, diabetes, and cancer [35,36]. However, the clinical efficacy of curcumin is significantly limited by its poor bioavailability. To overcome this limitation, curcumin can bind with transition metal ions, forming stable complexes that enhance its hydrolytic stability, particularly through the stabilization of its monoanionic enol form [34]. As a natural β-diketone derivative, curcumin is well-known for its strong ability to chelate metal ions such as Al³⁺, Mn²⁺, Fe³⁺, Cu²⁺, and Zn²⁺. Metal-curcumin complexes exhibit enhanced pharmacological effects, including anticancer, antioxidant, and neuroprotective properties [34]. For example, Zn(II)-curcumin complexes can inhibit the growth of hepatocellular carcinoma by modulating gut microbiota-mediated zinc homeostasis [10] (Fig. 1E). Additionally, there has been growing interest in utilizing metal-curcumin complexes as inhibitors of metal-induced neurotoxicity, with the aim of developing new diagnostic tools and therapeutic agents for Alzheimer's disease (AD), a neurodegenerative disorder affecting millions of patients worldwide [34].

All flavonoids share a common tricyclic carbon skeleton, consisting of three rings labeled A, B, and C. Among these, ring C is heterocyclic and contains an oxygen atom [30]. The typical structural framework of a flavonoid is illustrated in Fig. 1D. Flavonoids can be classified into different subgroups based on the nature and position of substituents, particularly the hydroxyl groups, on the rings. Common subgroups include flavanones, flavonols, flavones, and flavanonols [30]. Flavonoids derived from Chinese herbal extracts include well-known compounds such as baicalin, tea polyphenols, quercetin, and the flavonoids found in Ginkgo biloba. These compounds exhibit a wide range of bioactivities, contributing to their therapeutic potential in various health conditions.

In recent years, flavonoids have been reported to exhibit diverse biological activities, including anticancer, anti-inflammatory, anti-atherosclerotic, antioxidant, antidiabetic, antimutagenic, antithrombotic, vasodilatory, and antiviral properties [[37], [38], [39], [40], [41], [42], [43], [44], [45]]. These diverse pharmacological effects are attributed to the structural nature of flavonoids and their ability to interact with various cellular components, including the plasma membrane, cytoplasm, nucleus, and subcellular structures [30]. Flavonoids have also been shown to enhance the efficacy of chemotherapy when used in combination with anticancer drugs [46]. For example, complexes formed by quercetin and zinc exhibit significant antioxidant activity and anti-proliferative effects on tumor cells [47] (Fig. 1F). The absorption of quercetin is directly correlated with zinc content, which enhances its bioavailability and anticancer effects [47,48]. Baicalin, a flavonoid compound extracted from the dried roots of Scutellaria baicalensis, has been shown to possess numerous biological activities [49,50]. When coordinated with vanadium oxide, baicalin enhances the reactivity of the ligand, generating reactive oxygen species (ROS) that induce oxidative damage in tumor cells [51].

Tea polyphenols, primarily recognized as catechins, are a group of polyphenolic compounds found in tea leaves and belong to the flavonoid family, characterized by a basic α-phenyl-benzopyran structure [30] (Fig. 1D). Previous studies have demonstrated that tea polyphenols regulate lipid metabolism and exhibit potent antioxidant, anti-inflammatory, and anticancer effects [52]. With growing interest in their therapeutic potential, tea polyphenols have also been shown to alleviate type 2 diabetes and insulin resistance by enhancing glucose uptake in the muscles and adipocytes through translocating glucose transporter type 4 (GLUT4) translocation to the plasma membrane, primarily via activation of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway [53]. Additionally, tea polyphenols are prescribed for the treatment of various neurological disorders. For example, they can alleviate subarachnoid hemorrhage (SAH), an exceptional subtype of stroke by regulating the Ca²⁺-mitochondrial dynamic axis to protect mitochondrial function after SAH [54]. Green tea polyphenols, particularly epigallocatechin-3-gallate (EGCG), possess strong anti-amyloidogenic and neuroprotective properties, primarily due to their ability to target protein aggregates. This highlights the potential of polyphenols in the treatment of neurological diseases [55].

Tea polyphenols face intrinsic limitations for pharmaceutical applications due to their poor chemical stability, low solubility, and limited bioavailability. However, complexes formed by coordinating tea polyphenols with metal ions, such as tea polyphenol-iron and tea polyphenol-copper complexes, have demonstrated enhanced antioxidant, anticancer, and anti-inflammatory activities [52]. These metal-polyphenol complexes exhibit superior therapeutic effects compared to the native tea polyphenols, owing to the synergistic interaction between the bioactive constituents and the metal ions. For instance, the free radical scavenging capacity of tea polyphenols is significantly improved when coordinated with zinc. Additionally, zinc-coordinated tea polyphenols exhibit enhanced antibacterial activity against pathogens like Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) [56]. In another example, tea polyphenol-silver nanoparticle complexes have been developed for AD treatment. These complexes show a markedly increased binding affinity for amyloid plaques and exhibit enhanced antioxidant activity compared to unmodified tea polyphenols [55]. These findings suggest promising new avenues for using tea polyphenols in the management of neurodegenerative diseases.

Ginkgo flavonoids are natural plant compounds extracted from the leaves of Ginkgo biloba, known for their broad pharmacological activities, including antioxidant, anti-inflammatory, antitumor, and neuroprotective effects [[57], [58], [59]] (Fig. 1G). Recently, ginkgo flavonoid-metal ion complexes have garnered significant attention due to their enhanced drug efficacy and the introduction of new biological activities. The chemical groups in ginkgo flavonoids, such as hydroxyl and carboxyl groups, facilitate the formation of stable complexes with various metal ions, including iron, copper, zinc, and calcium. These metal complexes not only improve the antioxidant and anti-inflammatory properties of ginkgo flavonoids but also amplify their biological activities through the incorporation of metal ions. For example, ginkgo flavonoid-polypyridine metal complexes exhibit potent antitumor activity by inhibiting cancer cell proliferation through the disruption of key signaling pathways [60,61].

Collectively, the biological activities of flavonoid components in TCM, including antibacterial, antiviral, anti-inflammatory, antitumor, hypoglycemic, anti-ulcer, and antioxidant effects, are significantly enhanced when complexed with metal ions. This enhancement may result from structural alterations in the flavonoids upon complex formation, making them more accessible to disease targets and increasing their binding affinity. Alternatively, the synergistic interaction between the flavonoid components and metal ions may contribute to the enhanced activity. Furthermore, the conjugation of flavonoids with various metal ions can substantially reduce the cytotoxicity of these metal ions, both in vitro and in vivo. For example, aluminum-quercetin complexes have been shown to mitigate dietary aluminum overload [62].

2.2. Alkaloid-metal complexes

Alkaloid compounds, such as oxoglaucine, berberine, and matrine, are commonly conjugated with metal ions to enhance their anti-inflammatory, antiviral, and anticancer properties [[63], [64], [65], [66], [67], [68], [69], [70], [71]] (Figs. 2A–C). Oxoglaucine is an alkaloid recognized for its anticancer, antiplatelet aggregation, immunomodulatory, antifungal, and anti-inflammatory activities [72,73]. When complexed with metal ions, oxoglaucine can interact with DNA through intercalation. Compared to oxoglaucine or metal ions alone, the oxoglaucine-metal complexes exhibit significantly increased toxicity against tumor cell lines, demonstrating enhanced anticancer efficacy [72] (Figs. 2D and E).

Fig. 2.

Chemical structures of the different alkaloids. (A) Oxoglaucine. (B) Berberine. (C) Matrine. (D) Au-oxoglaucine. (E) Metal-oxoglaucine. (F) Metal-matrine complexes. (G) Metal-matrine complexes.

Berberine (2,3-methylenedioxy-9,10-dimethoxyprotoberberine chloride) is a yellow isoquinoline alkaloid with diverse therapeutic applications [73]. It has demonstrated significant anticancer efficacy by inhibiting cell proliferation, inducing cell cycle arrest, and triggering apoptosis [[74], [75], [76]]. Additionally, berberine exhibits antibacterial, antioxidant, and neuroprotective effects. For example, it regulates human metabolism by stimulating glycolysis, lowering blood glucose levels, and reversing insulin resistance through improved mitochondrial function, thereby achieving antidiabetic effects [77,78]. Despite these benefits, berberine's clinical use is hindered by its poor water solubility, suboptimal pharmacokinetic profile, and low bioavailability, which limit its therapeutic efficacy [79]. However, the formation of berberine-metal complexes significantly enhances its bioavailability and therapeutic effects. For instance, metal-mediated delivery of berberine selectively targets lung cancer cells, thereby improving its antineoplastic activity [80]. Specifically, berberine-silver complexes exhibit potent inhibitory effects on various cancer cell lines, while berberine-Zn complexes provide protection to the gastrointestinal tract against methotrexate-induced damage [81,82]. These advancements demonstrate the potential of berberine-metal complexes to overcome the limitations of native berberine and expand its clinical applications.

Matrine is commonly used in the treatment of viral hepatitis and cardiovascular diseases [83,84]. It has the ability to coordinate with metal ions such as Ga(III), Au(III), and Sn(IV) through its carbonyl oxygen atoms, significantly enhancing its antitumor activity while improving the biosafety profile of the drug [85] (Figs. 2F and G). This metal coordination strategy holds great potential for enhancing the therapeutic efficacy and safety of matrine in cancer treatment.

2.3. Polysaccharide-metal complexes

Polysaccharides are natural polymers composed of multiple monosaccharides linked by glycosidic bonds, typically exhibiting high molecular weights, often consisting of thousands of glucose units [86,87]. Due to their excellent biological activities (e.g., antioxidant properties), biodegradability, biosafety, and biocompatibility, polysaccharides have garnered significant attention for various therapeutic applications [88]. However, polysaccharides isolated directly from natural sources often exhibit weak or negligible biological activity [86]. Fortunately, coupling polysaccharides with metal ions can overcome these limitations, enhancing their efficacy and therapeutic potential.

Polysaccharide-metal complexes offer several advantages, such as improved solubility, stability, and bioavailability, with minimal side effects. For instance, polysaccharide-iron complexes have been recognized as an effective approach for iron supplementation, particularly for treating iron-deficiency anemia, owing to their high iron delivery efficiency [[89], [90], [91], [92]]. An example is the iron (III)-coupled Astragalus membranaceus polysaccharide, which exhibits enhanced bioavailability and antioxidant activity [92]. Similarly, Eucommia ulmoides polysaccharides (EUP) and chondroitin sulfate have demonstrated immunoenhancing effects, and their strontium-conjugated complexes show promising results in alleviating osteoarthritis symptoms by inhibiting inflammatory factor production and osteoclast formation [[93], [94], [95]]. Furthermore, Inonotus obliquus-chromium (III) complexes have been shown to effectively reduce blood glucose and lipid levels by downregulating α-amylase and α-glucosidase [96,97].

Polysaccharide-metal complexes also exhibit significant potential in anticancer therapy. For example, polysaccharide-platinum and polysaccharide-ruthenium complexes exhibit selective inhibition of certain cancer cell lines while maintaining high biocompatibility, positioning them as promising candidates for new polysaccharide-based anticancer drugs [98,99]. Additionally, polysaccharides derived from Aconitum kusnezoffii with the potential to conjugate iron or copper may produce inhibitory effects on various cancer cells [100]. These findings highlight the potential of polysaccharide-metal complexes in enhancing the therapeutic efficacy and expanding the clinical applications of polysaccharides.

2.4. Saponin-metal complexes

Saponins are naturally occurring, structurally and functionally diverse phytochemicals that are widely distributed in plants. Based on their chemical structure, saponins are primarily classified into two major categories: triterpenoid saponins and steroidal saponins [[101], [102], [103], [104]]. Among these, triterpenoid saponins are the most prevalent, consisting of 30 aglycones derived from pentacyclic triterpenoids [104] (Fig. 3A). Steroidal saponins, on the other hand, are steroidal glycosides formed by the combination of spirostane compounds and sugars. These molecules typically do not contain carboxyl groups and are generally neutral in nature [104] (Fig. 3B).

Fig. 3.

Chemical structures of the different saponins. (A) Triterpenoid saponins. (B) Steroid saponins.

Saponin compounds, particularly triterpenoid saponins, exhibit significant therapeutic potential, especially when coordinated with metal ions, enhancing their applications in anticancer and anti-inflammatory treatments [105,106]. For instance, ginsenoside-gold complexes improve the aqueous solubility and biodistribution of ginsenosides, thereby reducing the side effects associated with TCM and offering new insights into the medical application of ginsenosides [105]. Additionally, Co(II) and Cu(II) complexes of gypsogenin (L¹) or thiosemicarbazone glyoxime (L³H₂) demonstrate potent anticancer effects [106].

Following the discussion of saponin-metal complexes, it is important to compare and synthesize the distinct features of the four major categories of TCM-metal complexes introduced above. While each class, including polyphenol-, alkaloid-, polysaccharide-, and saponin-based, employs different ligand types, they all form complexes through coordination interactions between donor atoms (such as O or N) and metal ions, leading to enhanced physicochemical and biological properties. Polyphenols and alkaloids, as small-molecule compounds with well-defined functional groups, typically form stable chelate structures via hydroxyl, carbonyl, or nitrogen donors. These complexes often exhibit high redox activity, improved membrane permeability, and strong interactions with biomolecular targets. In contrast, polysaccharides and saponins are structurally larger and more complex. They provide multivalent or amphiphilic frameworks for metal coordination, which contributes to improved biocompatibility, sustained release behavior, and versatile formulation potential.

Functionally, polyphenol- and alkaloid-metal complexes are predominantly studied for their anticancer, antioxidant, and neuroprotective effects, owing to their strong interaction with cellular signaling pathways and oxidative stress mechanisms. Polysaccharide-based complexes show greater promise in immunomodulation and metabolic regulation, while saponin-metal complexes, with their membrane-disruptive and adjuvant-like characteristics, are increasingly investigated for anti-inflammatory and regenerative applications. Although these four categories differ in structural architecture and coordination patterns, they share the advantage of enhanced therapeutic efficacy through metal complexation. A clear understanding of their similarities and differences provides a basis for rational design of TCM-metal complexes for specific biomedical applications.

2.5. Formation mechanisms of TCM-metal complexes

The formation of TCM-metal complexes is primarily based on the coordination interactions between metal ions and specific functional groups present in bioactive compounds derived from TCM. These complexes are not formed by simple physical mixing; rather, they arise from chemical coordination processes in which ligands donate electron pairs to the vacant orbitals of metal ions, thereby forming coordination bonds. Such bonds are essential for the stability and bioactivity of the resulting complexes, often enhancing the therapeutic potential of the parent TCM compounds.

Many TCM-derived molecules, including polyphenols, flavonoids, alkaloids, polysaccharides, and saponins, possess functional groups such as hydroxyl, carbonyl, carboxyl, amino, and sulfhydryl moieties. These groups can serve as coordination sites, binding metal ions through various modes depending on the spatial arrangement and chemical properties of both the ligand and the metal. For instance, curcumin forms a bidentate chelate with metal ions via its β-diketone structure, which is highly effective in stabilizing transition metals like Cu²⁺ and Zn²⁺. Similarly, flavonoids with ortho-dihydroxyl substituents on aromatic rings can form stable five- or six-membered chelate rings with metal ions such as Fe³⁺ or Al³⁺, enhancing their antioxidant and anticancer properties.

The coordination structures that arise from these interactions can vary widely. In many cases, monodentate or bidentate coordination leads to the formation of simple metal-ligand complexes. In other instances, ligands may bridge two or more metal centers, forming polynuclear complexes or extended coordination networks. Some TCM-metal complexes further assemble into supramolecular structures, such as metal-phenolic networks (MPNs), which exhibit improved stability and multifunctional therapeutic effects. These structural differences significantly influence the physicochemical properties of the complexes, including their solubility, lipophilicity, redox behavior, and interaction with biological targets.

The type and strength of the coordination bonds formed depend on multiple factors, including the valency and electronic configuration of the metal ion, the number and nature of the donor atoms in the ligand, and environmental conditions such as pH and solvent polarity. For example, under mildly alkaline conditions, polyphenolic ligands like catechins and curcumin exhibit stronger chelation with metal ions due to the increased availability of deprotonated hydroxyl groups. Moreover, certain metal ions, such as Cu²⁺, Fe³⁺, and Zn²⁺, show a higher affinity for oxygen-rich ligands, forming stable octahedral or tetrahedral coordination geometries. A deeper understanding of these formation mechanisms and coordination structures is critical for advancing the design of TCM-metal complexes with improved efficacy and safety profiles. It also provides a structural basis for explaining the enhanced biological activity observed in many of these systems.

3. Applications of TCM-metal complexes in biomedical fields

As a novel class of bioactive compounds, TCM-metal complexes exhibit diverse and promising applications across various biomedical fields, including anticancer, antibacterial, antiviral, anti-inflammatory, immunomodulatory, and neuroprotective therapies. The conjugation of TCM components with metal ions significantly enhances the efficacy, stability, and bioavailability of the active ingredients. Additionally, some of these complexes demonstrate novel or amplified biological activities, further expanding their therapeutic potential.

3.1. Anti-cancer effects

In recent decades, cancer treatment has made significant strides with various therapeutic approaches, including surgery, radiotherapy, chemotherapy, and immunotherapy. Surgical intervention and radiation therapy are typically used for early-stage, localized, non-metastatic cancers, while chemotherapy and immunotherapy are employed for tumors that are resistant to surgery or radiation, or for metastatic cancers [107]. Although chemotherapeutic drugs are effective in inhibiting cancer cell proliferation, they often have adverse effects on normal cells, such as those in hair follicles, bone marrow, and the gastrointestinal tract, leading to both short- and long-term side effects [108,109]. Furthermore, the short half-life of many chemotherapeutic drugs limits their ability to reach and maintain therapeutic concentrations at tumor sites, thereby reducing their efficacy [110]. Additionally, some drugs are hindered by the blood-brain barrier (BBB), preventing them from effectively targeting brain tumors [111]. These issues contribute to drug resistance and the rapid spread of drugs into healthy tissues, emphasizing the need for new drug delivery strategies that balance efficacy and minimize side effects [112].

Recently, TCM-metal complexes have emerged as promising candidates in cancer treatment. By binding with metal ions, the active ingredients in TCM can enhance drug stability, bioavailability, and targeting capabilities. Metal complexes can modulate the intracellular oxidative state, increase the production of ROS, and trigger stress responses that activate apoptotic pathways. These properties make TCM-metal complexes potent in sensitizing cancer cells to therapy by amplifying the oxidative stress response [34,113]. Similarly, TCM-metal complexes formed by quercetin and vanadium exhibit significant anticancer effects across various tumor models, primarily by inducing ROS production and activating apoptotic pathways [114,115]. Furthermore, the Zn(II)-curcumin complex has demonstrated the ability to inhibit tumor growth by modulating zinc homeostasis in the gut microbiota, particularly in a hepatocellular carcinoma model [10].

In addition, TCM-metal complexes exhibit antiangiogenic potential in cancer therapy. Tumor growth depends on angiogenesis, the formation of new blood vessels to supply the growing tumor. TCM can inhibit tumor angiogenesis by suppressing the proliferation, migration, and tube formation of vascular endothelial cells, partly through downregulating vascular endothelial growth factor (VEGF) expression, a key regulator of new blood vessel formation [48]. TCM-metal complexes can also exert potent antitumor effects through direct interaction with DNA or by inhibiting enzyme activity, which induces cytotoxicity in various cancer models [9,68]. Metal ions can alter the three-dimensional structure of DNA by intercalating, embedding, or binding to the grooves of the DNA double helix, thereby disrupting DNA replication, transcription, and repair. For example, the berberine-silver complex has been shown to enhance DNA damage and inhibit the migration capacity of tumor cells [82]. Other metal ions such as copper, iron, and zinc, when complexed with active TCM ingredients, also mediate antitumor activities by interacting with DNA and affecting its integrity [60].

One of the key mechanisms by which TCM-metal complexes enhance their therapeutic effects is by improving cellular uptake. Metal ions coordinate with the active components of TCM to increase the complexes' affinity for cellular membranes, facilitating more efficient internalization into cancer cells [105]. For example, metal ions like zinc (Zn), copper (Cu), and manganese (Mn) form stable complexes with polyphenolic compounds, improving membrane affinity and promoting intracellular transport, which boosts therapeutic efficacy [10,30]. This targeted delivery not only boosts the drug's effectiveness but also minimizes side effects on normal tissue [101,116].

The development of TCM-metal complexes represents a promising avenue for anticancer therapy by enhancing apoptosis, inhibiting angiogenesis, and blocking metastasis. As pharmacological research on TCM deepens, TCM-metal complexes have demonstrated various antitumor mechanisms, including regulation of cell signaling pathways, stimulation of autophagy, promotion of apoptosis, and inhibition of neovascularization [31]. Notably, these complexes have been found to influence epigenetic regulation of cancer-related genes, particularly through non-coding RNA, such as microRNA (miRNA) and long non-coding RNAs (lncRNAs) [117]. Epigenetic alterations, such as DNA methylation, histone modification, chromatin remodeling, and miRNA regulation, are common in a variety of cancers [118]. These molecular mechanisms highlight the multi-level effects of TCM-metal complexes in cancer treatment, making them promising candidates for the development of future anticancer drugs.

3.2. Antibacterial and antiviral effects

TCM-metal complexes show considerable promise in the fields of antibacterial and antiviral applications. The coordination of metal ions with TCM compounds can significantly enhance their antimicrobial activity, making them effective against a wide range of bacterial and viral infections. This synergistic interaction between metal ions and the natural bioactive components of TCM results in improved pharmacological properties, including greater stability, higher bioavailability, and enhanced antimicrobial potency [104].

Metal ions, such as silver (Ag), zinc (Zn), and copper (Cu), are known for their inherent antibacterial properties [119]. When combined with TCM compounds, these ions further enhance the antimicrobial effects. For example, Ag-TCM complexes can boost antibacterial activity by disrupting bacterial cell membranes, inhibiting protein synthesis, cleaving DNA through nuclease activity, and inducing oxidative stress, which exacerbates cellular damage [10,56,[120], [121], [122]]. Similarly, flavonoid-metal complexes exhibit enhanced antibacterial properties due to structural changes in the ligand. These modifications increase the complex's ability to bind to DNA and proteins, disrupting essential cellular functions and amplifying antibacterial activity [30,123]. For instance, quercetin-metal complexes, such as quercetin-iron, bind to bacterial DNA more strongly in an intercalated fashion compared to uncomplexed quercetin, thereby enhancing the inhibitory effect against E. coli and S. aureus [122].

Beyond antibacterial properties, TCM-metal complexes also exhibit promising antiviral activity, particularly against RNA viruses like influenza and hepatitis. In the context of antiviral action, these complexes exert their effects by interfering with viral replication and inhibiting the activity of viral enzymes, showing strong performance against RNA viruses [124]. Both silver and zinc ions possess intrinsic antiviral properties, and their complexation with TCM compounds such as quercetin or saponins further enhances antiviral activity [47,125]. As emerging viral infections and drug-resistant strains continue to challenge traditional therapeutic approaches, TCM-metal complexes offer a novel and effective alternative for combating infectious diseases. These complexes are becoming increasingly important in both research and clinical applications for anti-infective therapies. This growing interest in TCM-metal complexes manifests their potential as valuable tools in the development of new antimicrobial and antiviral treatments.

3.3. Anti-inflammatory and immunomodulatory effects

Research into the anti-inflammatory and immunomodulatory effects of TCM-metal complexes has attracted widespread attention due to their potential therapeutic applications in chronic inflammatory and autoimmune diseases. The conjugation of metal ions with active components of TCM, such as alkaloids, saponins, and terpenoids, enables the regulation of immune activity and the release of inflammatory mediators, including cytokines, chemokines, and ROS. Luteolin-metal ion complexes, for example, exhibit notable anti-inflammatory properties, primarily attributed to their potent free radical scavenging activities [126]. Similarly, the Fritillaria ussuriensis polysaccharide (FUP)-zinc (Zn) complex demonstrates superior scavenging activity against hydroxyl radicals and superoxide anions compared to FUP alone, with the antioxidant activity increasing proportionally with zinc substitution levels [127].

TCM-metal complexes can also inhibit the activation of nuclear factor kappaB (NF-κB), a key transcription factor driving inflammatory responses. This inhibition leads to a reduced release of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 [128]. For instance, naringin-Cu complexes significantly lower nitrite levels and inflammatory cell counts in macrophage inflammation models, displaying much stronger immunomodulatory effects than native naringin [129]. Furthermore, copper and zinc complexes with saponins can regulate immune cell activation and differentiation, contributing to their anti-inflammatory effects. For example, baicalin-Zn complexes exhibit a markedly higher inflammation inhibition rate compared to zinc gluconate, a clinically used nonsteroidal anti-inflammatory drug [130,131].

Beyond their anti-inflammatory properties, TCM-metal complexes also exhibit significant immunomodulatory capabilities. These complexes can regulate the activation, differentiation, and proliferation of immune cells, influencing both innate and adaptive immune responses. For example, baicalin-Zn complexes enhance the activity of macrophages and T lymphocytes, demonstrating strong immunomodulatory potential [132]. Another example is the ginsenoside-Rh2-gold complex, which increases the production of interferon-gamma (IFN-γ) and enhances macrophage phagocytic activity, playing a vital role in maintaining immune homeostasis and offering potential therapeutic applications for immunodeficiency and autoimmune diseases [105,133].

The synergy between metal ions and TCM bioactive compounds amplifies their pharmacological effects and broadens their therapeutic potential in managing inflammatory and immune-related disorders. This combination offers several advantages over conventional treatments, including reduced side effects, improved bioavailability, and more targeted actions [82]. These complexes can mitigate excessive inflammation while restoring immune balance, positioning them as promising candidates for treating autoimmune diseases and other conditions characterized by dysregulated immune responses. As research on inflammation and immune-related diseases continues to advance, TCM-metal complexes are expected to provide innovative therapeutic options for anti-inflammatory treatment and autoimmune disease management. Their unique properties and mechanisms of action represent a significant step forward in developing more effective and safer treatments for these challenging conditions.

3.4. Neuroprotective effects

The prevention and treatment of neurodegenerative diseases are critical and highly appealing areas in modern medicine. TCM-metal complexes have demonstrated remarkable potential in neuroprotection, particularly in conditions such as AD and Parkinson's disease (PD) [34]. For example, zinc complexes with tea polyphenols have been shown to protect neurons by inhibiting oxidative stress, mitigating neuroinflammation, and preventing amyloid-beta (Aβ) plaque formation and free radical generation. These mechanisms effectively slow disease progression in AD and PD [30,35]. Another example is EGCG-coupled silver nanoparticles, which exhibit strong anti-amyloidogenic and neuroprotective activities [55]. Due to its lipophilic nature, curcumin can cross the BBB, destabilize pre-formed Aβ fibrils, bind to Aβ plaques, and inhibit further fibril formation. Metal-curcumin complexes enhance these anti-AD properties by selectively binding to Aβ plaques and mitigating their neurotoxic effects [134,135]. These findings highlight the potential of TCM-metal conjugates as novel therapeutic agents for treating neurodegenerative diseases.

Moreover, the combination of TCM bioactive compounds with metal ions can help restore nerve function and delay the progression of neurodegeneration by regulating neurotransmitter metabolism. For example, specific metal-TCM complexes modulate the balance of neurotransmitters such as dopamine, glutamate, and acetylcholine, which play critical roles in maintaining neural function and preventing neuronal damage. These complexes also enhance cognitive function and alleviate neurotoxic damage commonly associated with neurodegeneration. A key advantage of TCM-metal complexes is their ability to cross the BBB, enabling direct interaction with the central nervous system. This property allows them to address underlying pathological processes, such as oxidative stress, neuroinflammation, and protein misfolding, that are central to neurodegenerative diseases. As research into neuroprotection advances, TCM-metal complexes are emerging as promising candidates for drug development in this field. Their ability to target multiple pathogenic pathways offers a new direction for treating complex neurodegenerative disorders. Taking advantages of their unique properties and pharmacological benefits, TCM-metal complexes can be rationally designed and synthesized as next-generation neuroprotective therapeutics, opening new possibilities for improving outcomes in patients with neurodegenerative diseases [29].

3.5. Bioimaging

The use of nanosized contrast agents in bioimaging has significantly advanced the diagnosis of various diseases and deepened our understanding of biological processes at both cellular and subcellular levels. Among these, fluorescent nanoparticles, including quantum dots (QDs) and plasmonic nanoparticles, are the most widely utilized. These nanoparticles overcome several limitations associated with conventional small-molecule contrast agents, such as high cytotoxicity, limited photostability, and poor biocompatibility. Despite their inherent bioimaging capabilities, however, the imaging modalities of these nanoparticles are often constrained, failing to meet the increasingly complex demands of biomedical applications. To address this limitation, the development of multifunctional nanoplatforms that integrate diverse bioimaging capabilities has become a critical area of research.

The incorporation of radioactive metal ions into nanostructures, such as metal-phenolic networks (MPNs), has demonstrated considerable potential in enhancing imaging modalities. For instance, the integration of radioactive ⁶⁴Cu(II) ions into tannic acid (TA)-based MPNs (⁶⁴Cu(II)-TA MPNs) during their assembly process imparts both positron emission tomography (PET) and magnetic resonance imaging (MRI) functionalities. ⁶⁴Cu(II)-TA MPNs may serve as effective PET nanoagents, as confirmed by PET phantom imaging (Fig. 4A) [136]. In vivo biodistribution studies further indicated predominant accumulation of these capsules in the liver, with a smaller fraction observed in the spleen [136]. In another example, a novel class of photothermal materials, termed metal-ion-cross-linked TA (MITA), such as polydopamine nanovesicles (PNV)@Fe(III)-TA, has been reported to exhibit versatile photoresponsivity. These materials facilitate near-infrared (NIR) photothermal tumor ablation, photothermal imaging, and photoacoustic imaging, in addition to providing effective T1-weighted MRI capabilities (Fig. 4B) [137]. The role of metal ions is indispensable in advancing the fields of therapy and diagnosis, offering multifunctional capabilities that significantly enhance the performance of nanoplatforms in biomedical applications.

Fig. 4.

Positron emission tomography (PET) and magnetic resonance imaging (MRI) of traditional Chinese medicine (TCM)-metal complexes in tumor models. (A) Pseudo-color PET phantom image of the dispersions of 64Cu(II)-tannic acid (TA) capsules at various dilution ratios, and PET/computed tomography (CT) image of a mouse after the injection of ⁶⁴Cu(II)-TA [136]. (B) Schematic illustration of the synthesis of Fe(III)-TA complexes. In vivo T1-weighted magnetic resonance and pseudocolor images of 4T1 tumor-bearing mice before and 4 h after intravenous injection of polydopamine nanovesicles (PNV)@Fe(III)-TA, and T1- and T2-weighted MRIs and pseudocolor maps of 4T1 tumor-bearing mice before and 4 h after intravenous injection of PNV@Fe(III)-Mn(II)-TA. The tumor regions are indicated via yellow circles [137]. Reproduced from Refs. [136,137] with permission.

3.6. Other therapeutic effects

TCM-metal complexes have shown significant potential in promoting wound healing and tissue regeneration. For example, zinc-based complexes have been demonstrated to enhance fibroblast proliferation, collagen synthesis, and angiogenesis, which are the key processes essential for effective wound repair [10,82,138]. Zinc, known for its role in collagen formation and immune modulation, further accelerates the healing process by reducing inflammation and promoting cell migration. These complexes may be particularly beneficial for treating chronic wounds, diabetic ulcers, and aiding post-surgical recovery. Additionally, metal ions help stabilize the structure of TCM-derived bioactive compounds, enabling sustained therapeutic effects in tissue regeneration and wound management [33,34].

Beyond wound healing, TCM-metal complexes are being explored for their potential in treating metabolic diseases, such as diabetes, obesity, and lipid metabolism disorders. Metal ions like zinc and chromium, when combined with TCM compounds, can regulate critical metabolic pathways, including insulin signaling, glucose homeostasis, and fat oxidation [139,140]. For instance, the vanadium-kaempferol complex (administered intraperitoneally at 50 mg/kg) exhibited a significant hypoglycemic effect in alloxan-induced diabetic rats, achieving up to 69.6% reduction in serum glucose at 24 h post-administration. Notably, its efficacy was approximately three times greater than that of vanadium alone and superior to the free kaempferol ligand. Simply, a vanadium-kaempferol complex exhibits enhanced antihyperglycemic activity compared to the parent flavonoid in in vivo models [141]. Similarly, chromium-TCM complexes have demonstrated the ability to lower blood sugar and lipid levels by modulating enzymatic activities involved in carbohydrate and lipid metabolism [140]. These findings suggest that TCM-metal complexes could offer effective therapeutic options for managing metabolic disorders and mitigating the risks associated with obesity and diabetes.

The applications of TCM-metal complexes extend far beyond cancer therapy, showing promising results in wound healing, antiviral treatments, metabolic disorders, and neurodegenerative diseases. By incorporating metal ions, TCM active ingredients achieve enhanced bioactivity, stability, and targeted effects, making them versatile tools in modern biomedical therapies. Ongoing research into the mechanisms of these complexes, particularly their impacts on metabolic pathways, immune regulation, and cellular functions, holds promise for the development of novel treatments for a wide array of diseases. However, further studies are needed to optimize the synthesis, bioavailability, and clinical application of these complexes to unlock their full therapeutic potential.

4. Therapeutic mechanisms of TCM-metal complexes

TCM offers unique advantages and significant therapeutic effects in the treatment of various diseases. Both single TCM formulations and compound prescriptions have the ability to regulate multiple pathogenic targets and biological pathways. Due to the diverse and complex nature of TCM's active ingredients, the therapeutic mechanisms of TCM-metal complexes are correspondingly intricate and multifaceted. These complexes often act through a combination of synergistic interactions, enhancing the overall therapeutic efficacy while targeting a broad range of biological processes.

4.1. Regulation of cellular homeostasis

The therapeutic mechanisms of TCM-metal complexes primarily involve the regulation of cellular homeostasis, encompassing their effects on cell membranes, intracellular signaling pathways, and metabolic processes. By forming complexes with active components of TCM, metal ions significantly enhance the biological efficacy of these compounds. One key mechanism is the improved affinity of TCM-metal complexes for cell membranes, which facilitates enhanced cellular uptake. This increased permeability allows for more efficient delivery of therapeutic agents to target cells. For instance, quercetin-zinc complexes exhibit higher accumulation in cancer cells compared to quercetin alone, amplifying their therapeutic effects.

Additionally, TCM-metal complexes modulate cell signaling pathways to induce specific cellular responses, such as apoptosis, autophagy, or the inhibition of cancer cell proliferation. For example, curcumin-Zn(II) complexes regulate the intracellular redox state, inhibiting tumor cell growth. The elevated production of ROS induced by these complexes exacerbates oxidative stress, ultimately triggering apoptosis [10,142]. These combined mechanisms, including enhanced cellular uptake, modulation of membrane permeability, and targeted regulation of signaling pathways, grant TCM-metal complexes significant therapeutic potential in a wide range of applications, including anticancer and anti-inflammatory treatments [47].

Metal complexes can also inhibit cancer cell proliferation by targeting cell cycle progression, particularly at the G0/G1 or G2/M phases. Certain metal complexes interfere with intracellular signal transduction pathways, inhibiting key factors that activate tumor cell proliferation, such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and other signaling cascades [34,47,52,68,72,116]. For instance, the Mn(II)-emodin complex induces morphological changes in cells, arrests the cell cycle at the G0/G1 phase, and triggers apoptosis, ultimately decreasing tumor cell viability [26]. Numerous studies have demonstrated that TCM-metal complexes can induce apoptosis and inhibit cancer cell proliferation by activating signaling pathways associated with cell death [47,116]. For example, the vanadium-quercetin complex has been shown to attenuate mammary cancer by regulating the p53 and Akt/mechanistic target of rapamycin (mTOR) pathways, resulting in reduced cellular proliferation and increased apoptotic activity (Fig. 5A) [114]. Similarly, the Sm(III)-EGCG complex significantly reduces melanoma cell viability by modulating their metabolic pathways (Figs. 5B–D) [116].

Fig. 5.

Action mechanisms of vanadium-quercetin and SmIII-epigallocatechin-3-gallate (EGCG) complexes in cancer cells. (A) Apoptosis triggered by vanadium-quercetin complex [114]. (B) Schematic illustration of the synthesis of Sm(III)-EGCG nanocomplexes [116]. (C) Internalization of Sm(III)-EGCG into the melanoma cells, disassembly of green tea catechin and Sm³⁺ ions, and mitochondria-associated apoptosis [116]. (D) Therapeutic mechanisms of Sm(III)-EGCG in tumor treatment through the modulation of signaling pathways [116]. VEGF: vascular endothelial growth factor; Akt: protein kinase B; mTOR: mammalian target of rapamycin; PARP: poly(adenosine diphosphate (ADP)-ribose) polymerase. Reproduced from Refs. [114,116] with permission.

4.2. Interaction with proteins

The effective binding of TCM-metal complexes to proteins is critical for their biological activity. Metal ions, when coordinated with functional groups (such as hydroxyl and carboxyl groups) in the active components of TCM, form stable complexes that can interact with a wide range of intracellular and extracellular proteins. These interactions enable TCM-metal complexes to influence various biological processes by modulating enzymatic activity and altering metabolic pathways. For example, metal-polyphenol complexes can inhibit the activity of metalloenzymes in cancer cells, thereby suppressing tumor growth and metastasis [33]. Additionally, TCM-metal complexes can bind to signal transduction proteins, regulating key cellular processes such as proliferation, differentiation, and immune responses. A specific instance is the baicalin-Zn complex, which enhances the antioxidant capacity of cells by binding to superoxide dismutase (SOD). This interaction helps mitigate oxidative stress, reducing cellular damage [28,29]. In summary, TCM-metal complexes exert multi-faceted therapeutic effects by interacting with and modulating the function of intrinsic proteins, influencing various biochemical pathways, and improving cellular health.

4.3. Interaction with DNA

The interaction of TCM-metal complexes with DNA primarily involves their ability to bind to the DNA double helix through intercalation, groove binding, or direct interaction, thereby influencing DNA replication, transcription, and repair. Most TCM-metal complexes exhibit a high affinity for DNA, with their binding mode significantly affecting their biological activity, including cytotoxic characteristics. The specific binding sites on DNA, whether the major or minor groove or through intercalation, play a critical role in determining whether these complexes stabilize or disrupt the double helix structure.

For instance, flavonoid-metal ion complexes are known to interact with DNA via intercalation or groove binding. The naringin-copper complex has been suggested to preferentially bind to the minor groove, although conclusive experimental evidence confirming this specific binding site is still lacking [143]. The hydrophobicity of the flavin ring, attributed to the malonyl-CoA framework, appears to influence its binding orientation and affinity. Furthermore, fluorescence quenching of ethidium bromide by naringenin-copper and naringenin-zinc complexes suggests that these complexes act as intercalators, competitively displacing ethidium bromide from DNA [144,145]. Similarly, oxoglaucine-metal complexes primarily interact with DNA through intercalation [72]. The berberine-zinc complex exemplifies how binding to DNA can enhance drug stability and antitumor activity by altering DNA structure [82]. The data reveal that most TCM-metal complexes demonstrate an affinity for DNA, with binding modes that include both groove binding and intercalation. The energy-minimized configurations for nine distinct flavonoid-metal ion complexes reveal that each complex interacts with DNA at specific binding sites, further highlighting their structural diversity and potential therapeutic applications [30].

Many metal ions can form coordination bonds with the phosphate groups or nucleotide bases in DNA molecules, leading to alterations in the secondary structure of DNA. These interactions can hinder key biological processes such as DNA replication and transcription. The ability of TCM-metal complexes to interact with DNA represents an important mechanism underlying their pharmacological effects, contributing to their potential in treating various critical diseases. However, further research is essential to elucidate the precise nature and biological implications of these interactions. A deeper understanding of how TCM-metal complexes influence DNA structure and function will provide valuable insights into their therapeutic potential, enabling the design of more effective and targeted treatments. These findings collectively emphasize the versatility of TCM-metal complexes in targeting DNA, offering valuable insights for their development as therapeutic agents in applications such as anticancer treatments.

4.4. Impact of metal ions and TCM ligands on therapeutic mechanisms

The therapeutic mechanisms of TCM-metal complexes are fundamentally influenced by the dual contributions of both metal ions and the TCM-derived ligands. These components work in synergy, with each playing distinct yet complementary roles in modulating pharmacological outcomes. While metal ions often serve as structural and functional enhancers, the TCM ligands themselves possess intrinsic biological activities that significantly contribute to the overall therapeutic efficacy of the complex.

Metal ions influence therapeutic mechanisms through several pathways. They can enhance the physicochemical properties of TCM ligands, such as solubility, stability, and lipophilicity, thereby improving bioavailability and cellular uptake. In disease contexts where membrane permeability and enzymatic degradation are limiting factors, these improvements are particularly beneficial. In addition, many metal ions, particularly redox-active species like Cu²⁺, Fe²⁺/Fe³⁺, and Mn²⁺, participate directly in biological processes by generating ROS. These ROS can induce oxidative stress, disrupt mitochondrial function, and trigger apoptosis, especially in cancer cells. Meanwhile, other metal ions such as Zn²⁺ and Mg²⁺ modulate the activity of enzymes, transcription factors, or signaling pathways involved in inflammation, immunity, and cell survival.

Equally important are the TCM ligands, which are not merely passive carriers but biologically active agents with therapeutic properties of their own. Polyphenols (e.g., quercetin and curcumin), alkaloids (e.g., berberine and matrine), polysaccharides, and saponins exhibit a wide range of pharmacological effects including antioxidant, anti-inflammatory, immunomodulatory, and antitumor activities. These compounds often act on key molecular targets such as NF-κB, PI3K/Akt, and MAPK pathways, or regulate cytokine production and apoptotic signaling. When these ligands form coordination complexes with metal ions, their bioactivity can be enhanced or redirected. For example, curcumin-metal complexes have shown stronger cytotoxicity and ROS induction than curcumin alone, while baicalin-metal complexes demonstrate improved radical scavenging capacity and membrane interaction.

Moreover, the coordination between TCM ligands and metal ions often results in altered pharmacodynamics and pharmacokinetics, including prolonged circulation time, targeted delivery, and reduced systemic toxicity. The nature of the ligand-metal interaction, such as chelation strength, geometry, and stability, can influence not only the cellular uptake route but also the intracellular fate and release profile of the complex. Conclusively, the therapeutic mechanisms of TCM-metal complexes are governed by the cooperative action of both the metal center and the bioactive ligand. Metal ions confer structural and functional enhancements, while TCM ligands provide target specificity and intrinsic biological activity. A nuanced understanding of this interaction is essential for the rational design of TCM-metal complexes with optimized therapeutic profiles for specific diseases.

5. Limitations and future perspectives

The advantages of TCM-metal complexes lie in their diverse pharmacological effects, broad range of natural sources, and favorable biocompatibility. The inherent therapeutic properties of TCM, including anticancer, anti-inflammatory, and antimicrobial effects, provide substantial potential for biomedical applications. When combined with metal ions, these complexes benefit from enhanced drug targeting, improved stability, and increased therapeutic efficacy. Ongoing research on the active components of TCM and the coordination chemistry of metal ions continues to optimize these complexes, aiming to improve their effectiveness in treating complex diseases (Table 1) [72,85,99,106,126,143,[145], [146], [147], [148], [149]].

Table 1.

Summary of current traditional Chinese medicine (TCM)-metal ion complexes.

TCM-metal ion complexes	TCM	Metal ion	Biological activity	Applications	Refs.
Alkaloid-metal	Oxoglaucine	Zn(II)	DNA binding and antitumor	Tumor treatment and immunomodulation	[72]
Alkaloid-metal	Quinolizidine alkaloid matrine	Ga(III)	DNA binding and antitumor	Tumor treatment and immunomodulation	[85]
		Au(III)	DNA binding and antitumor	Tumor treatment and immunomodulation	[85]
		Sn(IV)	DNA binding and antitumor	Tumor treatment and immunomodulation	[85]
Polysaccharides-metal	Lycium barbarum polysaccharide	Pt(II)	DNA binding and antitumor	Tumor treatment and immunomodulation	[99]
Saponin-metal	Gypsogenin	Cu(II)	Antitumor	Tumor treatment	[106]
		Co(II)	Antitumor	Tumor treatment	[106]
Polyphenol-metal	Luteolin	Ho(III)	Anti-inflammatory	Anti-inflammation and antioxidation	[126]
		Yb(III)	Anti-inflammatory		[126]
		Lu(III)	Anti-inflammatory		[126]
		Y(III)	Anti-inflammatory		[126]
Polyphenol-metal	Naringin	Cu(II)	Anti-oxidation, anti-inflammatory, antitumor, and DNA binding	Tumor treatment, anti-inflammation, and antioxidation	[143]
Polyphenol-metal	Apigenin	Cu(II)	Antitumor, anti-oxidation, and DNA binding	Tumor treatment and antioxidation	[145]
Polyphenol-metal	Hesperitin	Cu(II)	DNA binding, antitumor, and Anti-oxidation	Tumor treatment and antioxidation	[145,146]
Polyphenol-metal	Hesperitin	Zn(II)	DNA binding	Antioxidation	[146]
Polyphenol-metal	Hesperitin	Ni(II)	DNA binding	Antioxidation	[146]
Polyphenol-metal	Hesperitin	Ln(III)	DNA binding	Antioxidation	[147]
Polyphenol-metal	Naringin	Fe(III)	Suppression of peroxidation and anti-oxidation	Immunomodulation and anti-inflammation	[148]
Polyphenol-metal	Hesperidin	Cu(II)	Anticoagulant	Cardiovascular diseases treatment, antithrombotic therapy, and platelet function regulation	[149]
		Al(III)	Anticoagulant		[149]

Despite these promising aspects, several limitations hinder the clinical application of TCM-metal complexes. First, the potential cytotoxicity of certain metal ions remains a major concern. For example, transition metal ions like Cu²⁺ and Fe³⁺ are highly reactive and may induce oxidative stress, leading to damage in normal tissues and organs. Although these metal ions are useful in cancer therapy by inducing apoptosis in tumor cells, their non-target toxicity to healthy cells needs to be carefully controlled. Second, the synthesis of TCM-metal complexes often involves complex methods, such as pH-controlled coordination or hydrothermal synthesis, which can be difficult to scale for large-scale production. This poses challenges for the commercial feasibility of these complexes. Additionally, the in vivo stability and controlled release mechanisms of metal ions in the body need further optimization. Without precise control over these factors, the bioavailability and safety profile of TCM-metal complexes may be compromised. Furthermore, balancing efficacy and toxicity remains a significant challenge. While metal ions can enhance the pharmacological effects of TCM ligands, their cytotoxicity or potential for organ toxicity must be minimized. Efforts to optimize drug delivery systems, such as nanoparticles or micelles, may offer a solution by providing targeted release mechanisms and reducing systemic exposure to toxic metal ions.

To address these challenges, future research should focus on the development of pharmacologically active metal complexes with well-defined and stable coordination structures. The careful selection of metal ions that possess lower toxicity, such as Zn²⁺ and Mg²⁺, in combination with TCM ligands could enhance therapeutic outcomes while minimizing side effects. Moreover, nanotechnology holds great promise in overcoming the current limitations of TCM-metal complexes by enabling the precise delivery of these complexes to target tissues. Nanocarriers could improve the bioavailability, solubility, and stability of the complexes, allowing for controlled release and reducing the risk of off-target effects. Advanced strategies such as surface modification of nanoparticles with specific TCM-derived ligands could further enhance the targeting of cancer cells or infected tissues.

In summary, TCM-metal complexes represent a highly promising class of therapeutic agents with significant potential for clinical applications in oncology, infectious diseases, and inflammatory conditions. As research into the integration of TCM ligands with metal ions advances, there is substantial opportunity to develop novel treatments for critical diseases. While challenges related to toxicity, stability, and synthesis remain, innovations in nanotechnology, metal ion selection, and targeted drug delivery systems are likely to expand the clinical utility of these complexes and enhance their therapeutic profiles.

6. Conclusions

TCM-metal complexes represent a novel therapeutic strategy that combines the bioactivity of TCM constituents with the functional versatility of metal ions. This review provides a comprehensive overview of their classification, coordination chemistry, pharmacological applications, and therapeutic mechanisms. By organizing complexes according to ligand types, including polyphenols, alkaloids, polysaccharides, and saponins, we highlight how distinct coordination behaviors influence biological activity and pharmacokinetics. A key contribution of this work is the comparative insight into how metal coordination enhances or alters the therapeutic effects of TCM ligands, improving solubility, redox behavior, and target specificity. This review offers a clearer understanding of the synergy between metal ions and bioactive plant-derived molecules. Importantly, we address major challenges in the field, including coordination variability, potential toxicity, and poor in vivo stability, and suggest solutions such as nanotechnology-enabled delivery and rational ligand design. Overall, this review consolidates current knowledge while providing a forward-looking framework for advancing TCM-metal complexes as multifunctional therapeutics. Their potential for application in cancer, infection, and inflammatory diseases highlights the importance of continued interdisciplinary research in this emerging area.

CRediT authorship contribution statement

Minyu Han: Writing – original draft, Investigation, Formal analysis. Jinning Mao: Validation, Supervision, Investigation. Guodong Liu: Writing – review & editing, Supervision, Project administration, Funding acquisition. Peng Xue: Writing – review & editing, Supervision, Project administration, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following is the Supplementary data to this article: