An encounter between metal ions and natural products: natural products-coordinated metal ions for the diagnosis and treatment of tumors

Abstract

Natural products-coordinated metal ions to form the nanomedicines are in the spotlight for cancer therapy. Some natural products could be coordinated with metal ions forming nanomedicines via simple and green environmental self-assembly, which not only improved the bioavailability of natural products, but also conferred multiple therapeutic modalities and multimodal imaging. On the one hand, in the weak acidity, glutathione (GSH) and hydrogen peroxide (H₂O₂) overexpression of tumor microenvironment (TME), such carrier-free nanomedicines could be further enhanced the therapeutic effect via optimizing the species of metal ions. On the other hand, nanomedicines could exert the precise treatment of tumor under the guidance of multiple imaging. Hence, this review summarized the research progress in recent years on the application of natural product-coordinated metal ions in cancer therapy. In addition, the prospects and challenges for the application of natural product-coordinated metal ions were discussed, especially how to improve targeting ability and stability and assess the safety of metal ions, so as to facilitate the clinical translation and application of natural product-coordinated metal ions nanomedicines.

Graphical Abstract

Introduction

Cancer has become a serious challenge to human health and survival. Moreover, complications such as infection, hemorrhage, acidosis, and hypokalemia during tumor development directly affect human health [1, 2]. Traditional therapies such as chemotherapy and radiation present side effects that are impossible to ignore. Such as hematologic toxicity, gastrointestinal reaction, liver toxicity and nervous system toxicity. Therefore, it is urgent to explore effective and safe treatment methods [3]. Recently, nanomedicines formed by natural product-coordinated metal ions have attracted great attention in cancer diagnostics and therapy owing to improve the bioavailability and safety of antitumor drugs, possess multiple therapeutic modalities for precise treatment under imaging monitoring [4–6].

Natural products are chemical components or their metabolites in animals, plants and microorganisms, characterized by abundant sources and novel structures, which are widely recognized for their accessibility, effective activity and safety. Over the years, it has been a valuable and useful source of anticancer agents [7]. Among the various treatments for cancer, traditional Chinese medicine and natural products have an exceptional anti-cancer effect due to their unique advantages of high efficiency and minor side effects [8]. Currently, natural products have been employed in the green synthesis of nanomaterials to reduce the carbon footprint of the synthesis process. The green synthesis of nanomaterials prepared from natural products is low-cost, less polluting and safe for the environment and human health compared to conventional materials [9]. Notably, prepared green nanomaterials based on natural products also could be applied for the treatment of diseases [10]. Several studies revealed that natural products could remove cancer cells by targeting the tumor immune microenvironment, modulating the cell cycle and promoting apoptosis [11, 12].

Metal ions are essential for the life activities of the vast majority of organisms and, are required to participate in their metabolic processes in order to maintain major physiological functions. It plays an important role in many complex physiological and biochemical processes such as cell division, material transport, metabolic regulation, etc. [13]. With the emergence of the star anti-cancer drug cisplatin, transition metal complexes are also considered to be an effective cancer cell inhibitor [14]. For example, the first-line systemic chemotherapeutic drug doxorubicin (DOX) possesses the characteristics of diagnosis and treatment after coordination with transition metal Fe or Cu. It not only improves the aqueous solubility and bioavailability of DOX, but also enables it to be utilized in multiple treatments and multimodal imaging [15, 16]. Therefore, there are great prospects in the treatment of cancer via the coordination of natural products with metal ions.

Currently, synergistic therapies such as chemodynamic therapy (CDT), photodynamic therapy (PDT) and photothermal therapy (PTT) based on natural products-coordinated metal ions offer new options for the treatment of tumors [17–19]. Multimodal imaging integrates optical, electrical, magnetic, and nuclide imaging paradigms to achieve cross-scale imaging from the molecular level to the in vivo level and from the angstrom to the meter. Multimodal imaging has been extensively applied in oncology research and other cutting-edge life science fields [20–22]. For example, it could be applied for treatment detection and efficacy assessment of tumors, which was conducive to the realization of precision therapy [23]. In addition, imaging detection was used for tracing of drugs and obtaining the entire drug delivery process. Some imaging detections have been applied in targeting and accumulating primary and metastatic tumors. Therefore, the development of imaging-guided drug delivery as well as the combination of multiple imaging modalities for nanomedicine tracing as well as for tumor diagnosis and therapy is of great significance [24]. After coordinated metal ions, the nanomedicines possess multimodal imaging function includes magnetic resonance imaging (MRI), photothermal imaging (PTI), photoacoustic imaging (PAI), and fluorescence imaging (FI), etc., which enables precise diagnosis and treatment of tumors guided by the combination of multiple imaging modalities. Accordingly, combining the respective advantages of natural products and metal ions, coordination assembly not only features simple and green synthesis and breaks through the limitations of traditional synthesis methods, but also highlights the application of multi-pathway precision therapy guided by multimodal imaging. Obviously, the natural product-coordinated metal ion nanomedicines offer new strategies for tumor therapy.

In this review, we systematically summarized the coordination assembly of natural products with essential metal elements in human body, mainly including therapeutic and biological imaging modalities (Fig. 1). In addition, we provided insights into the potential safety problem, current problems and future prospects of metal coordination. This review provided a scientific basis and outlook for the synthesis of nanomedicines from natural product-coordinated metal ions for the treatment of cancer.

Fig. 1.

The therapeutic and biological imaging modalities of metal-coordinated natural product nanoparticles, including multiple therapeutic modalities (CT/ PDT/ PTT/ SDT/ ICD/ GT/ CDT) and multiple biological imaging modalities (MRI/ PAI/ PTI/ FI)

Self-assembly of natural product-coordinated essential metal ions for cancer therapy and diagnosis

With the gradual maturation of nanotechnology, nanomedicines synthesized from natural product-coordinated metal ions are attracting more attention due to their environmentally-friendly synthesis, controllability of size and morphology, stability in body circulation, high drug loading rate and the advantages of multi-pathway, multi-target therapeutics and multi-modal imaging [25]. Current studies have demonstrated the high safety and biocompatibility of supramolecular nanoparticles based on coordination-induced self-assembly. Natural product-coordinated metal ions possessed the performance of responding to the TME for targeted drug release [25, 26]. Self-assembly of natural products with essential metal elements in the human body can not only play the chemotherapeutic effect of natural products, but also improve the microenvironment of the tumor through exogenous supplementation of metal elements to achieve the therapeutic purpose. Essential metal elements include calcium (Ca), magnesium (Mg), iron (Fe), copper (Cu), manganese (Mn), zinc (Zn), cobalt (Co), molybdenum (Mo), nickel (Ni), vanadium (V) and tin (Sn). These elements are essential in the human body and participate in various biochemical reactions, such as energy production, cell division, and immune function, etc. The following section describes the coordination applications of natural products with these metal elements.

Natural product-coordinated Ca²⁺ self-assembly

Calcium, as a macronutrient in the body, is a major component of human bones and teeth. It controls a variety of cellular processes and is essential for maintaining bone health, normal nerve conduction and muscle contraction [27]. Currently, there were few studies on coordination self-assembly nanoparticles of natural products with Ca²⁺.

In recent years, Yang et al. constructed a composite hydrogel consisting of Au nanocluster and P. aeruginosa microcystis leaf extract by a one-step method along with redox and coordination reactions. They found the synthesized hydrogel demonstrated excellent photothermal performance and significant tumor cell inhibitory activity. In vivo PTI also demonstrated that the hydrogel could be effectively enriched into the tumor site and showed a significant temperature increase under laser irradiation. At the end of the treatment, they noticed that the hydrogel significantly inhibited tumor growth. Importantly, histopathological sections indicated no obvious adverse effects. In conclusion, the hydrogel could coordinate with Ca²⁺ present in the tumor environment, which not only reduced the toxicity and side-effects, but also accumulated in high concentration in the lesion and enhanced the anticancer ability [28]. Representative natural products coordinated with Ca²⁺ were summarized in Table 1.

Table 1.

Representative natural products coordinated with Ca²⁺ and Mg²⁺

NO	Natural Products	Metal ions	Preparation	TME Response	Size	Treatment	Bioimaging	Reference
1	Premna microphylla leaf extract, PMLE	Ca2+	In-vivo assembly	NIR, pH	–	PTT/PDT	PTI	[28]
2	Gallic acid, GA	Mg2+	Hydrothermal	pH	–	CT/CDT/PTT	–	[29]

Natural product-coordinated Mg²⁺ self-assembly

Magnesium is an essential element for sustaining life activities in human body and exerts miraculous functions in regulating nerve, muscle activities and enhancing endurance. Anu et al. developed a cannabidiol–loaded Mg–gallate metal–organic framework via Mg²⁺ coordinated with gallic acid (GA) and loaded with cannabidiol (CBD) for the study of anticancer effects in rat glioma brain cancer (C6) cell lines. The fabricated nanomedicines achieved the rapid release of GA and CBD under acidic conditions in vitro confirmed TME response and safety to normal tissues. It could provide two potential anticancer agents (CBD and GA) to the cancer cells at the same time and displayed greater inhibition of C6 glioblastoma cells [29]. Representative natural products coordinated with Mg²⁺ were summarized in Table 1.

Natural product-coordinated Fe^2+/3+ self-assembly

Iron, the most abundant trace element in the human body, is involved in regulating various physiological functions, such as body metabolism, nutrient synthesis, and regulation of immune function. In recent years, self-assembled structures of natural products coordinated with Fe^2+/3+ have been widely investigated and applied in the field of oncology. Currently, extensive researches have confirmed the effect of Fe^2+/3+ as a catalyst of the Fenton reaction in CDT, which converts H₂O₂ in the endogenous TME into ·OH to kill tumor cells. Furthermore, the introduction of Fe³⁺ depleted high levels of GSH in the tumor environment and enhanced oxidative stress. Therefore, enhanced intracellular CDT in tumor cells by introducing exogenous Fe^2+/3+ is a promising therapeutic approach. In addition to above potential anticancer applications, iron-containing nanoparticles served as contrast agents for PAI and MRI. Furthermore, Fe^2+/3+ coordination was demonstrated to possess excellent photothermal properties for applications in PTT and bioimaging.

In recent years, a great number of traditional Chinese medicinal ingredients were also found to possess the ability to coordinate with metals, especially polyphenolic compounds. Tannic acid (TA), a natural product with the ability to coordinate with metal ions, was listed as a food additive by the US Food and Drug Administration [30]. Currently, numerous studies reported that the coordination of TA with Fe³⁺ accelerated the Fenton reaction and enhanced the generation of ·OH, which could serve as a carrier for CDT. In addition, TA-Fe³⁺ complexes presented photothermal properties and imaging functions [31]. Luo et al. prepared DOX-encapsulated nanoparticles by directly attaching Fe³⁺ and TA complexes to DOX. Rupture in the tumor environment released DOX for CT, and the introduction of Fe³⁺ depleted Adenosine triphosphate (ATP) further enhanced the CT effect. The nanoparticles combined with PTT for 14 days resulted in a significant improvement of tumor volume. Moreover, it could be used for MRI, PAI and PTI (Fig. 2a) [32]. Li et al. prepared a nanoplatform for dual-mode MRI-guided combined chemo-photothermal anti-cancer therapy. Fe-TA was adhered to the outer layer of polydopamine (PDA)-modified Fe₂O₃ to form a coordination network magnetic nanoparticles with effective T1/T2 bimodal MRI properties. This nanoparticle not only possessed significant photothermal properties, but also served as an effective delivery platform for the chemotherapeutic drug DOX [33]. The combination of photothermal and immunotherapy provided a great advantage in the treatment of cancer. In another study, TA were attached to the poly (lactic-co-glycolic acid), (PLGA) surface after coordination with Fe³⁺. The nanoparticles displayed excellent photothermal conversion efficiency and photothermal stability under laser irradiation. The photothermal treatment could induce the release of Damage Associated Molecular Patterns (DAMPs) from effectively triggering the immune response and promoting the maturation of DC cells. The experimental results revealed that the tumor site warmed up significantly after laser irradiation, which effectively inhibited in situ tumor growth. In addition, the distal tumor was also obviously suppressed due to the stimulation of immunogenetics by the laser. The combination of photothermal and immunotherapy provided a new platform for in situ, distal and metastatic tumors [34]. Besides, Tian et al. designed an O₂ self-supplying catalytic nanoparticle for cascade metabolic-CDT based on TA and Fe³⁺ coordination-loaded lactate oxidase via dual depletion of lactate and ATP as well as generation of ·OH [35]. This nano-formulation enables cascade metabolic-CDT. Meanwhile, the TA-coordinated Fe³⁺ appeared photoacoustic signaling that could serve as a guide to improve the accuracy of the therapy.

Fig. 2.

Some representative natural products coordinated with Fe^3+/2+. a The treatment and bioimaging of tannic acid-coordination Fe³⁺ encapsuled DOX NPs.

Copyright 2022, Ivyspring International Publisher. b The TME response, treatment and bioimaging of gallic acid-coordination Fe³⁺ and then was encapsuled with PEG-PLGA. Copyright 2022, Dove Medical Press Ltd. c The treatment and bioimaging of ellagic acid -coordination Fe³⁺ and then was encapsuled with BSA. Copyright 2022, Dove Medical Press Ltd. d The design, mechanism, treatment and bioimaging of PTH@FEP. Copyright 2020, American Chemical Society

Zhang et al. designed a nanoparticle consisting of gallic acid (GA) coordinated with Fe³⁺ (Fig. 2b). It possessed satisfactory photothermal stability properties and favorable photothermal conversion efficiency; the nanoparticle prepared was released only under TME. In addition, the nanoparticle could be applied for MRI, which enabled localization of tumor location and volume. The apoptosis-inducing effect of the nanoparticle was also demonstrated at the cellular level. This study enabled CT and PTT synergistic strategy mediated by MRI [36]. On this basis, Liu et al. loaded the DOX into hollow Fe-GA/ bovine serum albumin(BSA), which produced ·OH by depleting intracellular high glutathione (GSH) and triggering the Fenton reaction for CT combined with CDT [37]. Similarly, ellagic acid-coordination Fe³⁺ possessed favorable photothermal properties, and this nanoparticle could massively enrich at the tumor site for MRI and PAI (Fig. 2c) [38].

Dopamine (DA), as a polyphenol compound, had the ability to chelate iron. At the same time, it could be easily polymerized into PDA and widely applied in the nano delivery field. Chen et al. developed a degradable metal complex containing Fe³⁺-DA (FEP) core and HA-crosslinked Cisplatin (CDDP) shell (PTH), which amplified in situ toxicity of ROS production through synergistic interaction of CDDP and Fe³⁺. CDDP and Fe³⁺ were continuously released in the TME, which synergistically enhance the effect of CDT and CT through depleting GSH, inhibiting the expression of GPX4, up-regulating expression of p53 and NOXs. In addition, this metal complex exhibited excellent photothermal properties owing to the presence of FEP core, which accelerated the Fenton reaction while playing a role in the PTT effect (Fig. 2d) [39]. Furthermore, Zhang et al. designed the simultaneous application of Fe³⁺ and DA coordination with polyvinylpyrrolidone (PVP) to improve the dispersion stability of the nanoparticles showed good photothermal effects, which allowed for in vitro and in vivo PTI and PAI [40].

Anti-cancer drug coordinated with metal ions conferred multiple therapeutic pathways. Wang et al. synthesized hyaluronic acid (HA)-modified Fe³⁺-porphyrin (TCPP)-coordinated nanoparticles (FT@HA NPs) using a one-pot method that exhibited FI and MRI properties. The release of Fe³⁺ and TCPP in the low pH and high GSH tumor microenvironment of the tumor triggered GSH depletion and Fenton reaction. At the same time, the fluorescence and PDT effects of TCPP were activated. MRI and FI results revealed the enrichment and metabolism of the nanomedicine at the tumor site, thus enabling the monitoring of the in vivo processes of FT@HA NPs. FT@HA NPs could precisely exert therapeutic effects under the guidance of dual-mode imaging [41]. This nanoplatform integrated PDT, MRI and FI, which highlighted the synergistic therapeutic and imaging effects generated by the coordination of natural products with metal ions. In addition, Xu et al. fabricated a nanoparticle with acid-responsive and ultrasound-enhanced release response, which synthesized from hematoporphyrin monomethyl ether-coordination Fe³⁺-loaded DOX. The phospholipid modification was more conducive to tumor-targeting enrichment and showed significant tumor inhibitory effects [42]. For systemic delivery and prolonged circulation time, Liang et al. designed a nanoparticle based on DOX-coordination Fe³⁺ and then camouflaged with erythrocyte membranes. It achieved excellent in vitro and in vivo antitumor therapeutic effects [15]. In 2022, Fan et al. designed an anti-angiogenic nanoparticle, which was self-assembled from the chemicals pemetrexed, Fe³⁺ and hyoscine B via coordination-driven self-assembly. The nanoparticle enabled visualized self-targeting under MRI monitoring for effective tumor therapy by inhibiting angiogenesis [43].

In 2021, Chen et al. developed a carrier-free nanoparticle consisting of Fe³⁺ coordinated to artemisinin (ART). Fe³⁺-ART NPs were employed for MRI and CDT. Interestingly, this was a therapeutic strategy to amplify oxidative stress in vivo, which was independent of H₂O₂ concentration. Fe³⁺ was released with ART in the TME, where Fe³⁺ was reduced to Fe²⁺ by GSH. Then Fe²⁺ catalyzed the breakage of the peroxide bridge bond of ART generating more reactive oxygen species (ROS), thus inducing cell death. In the meanwhile, the depletion of reduced GSH further reduced the antioxidant capacity of tumor cells, exerting a synergistic therapeutic effect. In addition, it was smoothly metabolized in vivo and exerted a favorable biosafety profile due to its biodegradability (Fig. 3a) [44]. Similarly, Li et al. attached TA and Fe²⁺ to ART-coated ZIF skeletons, which caused high levels of ROS and MDA and reduced GSH levels in the cells after treatment. In vitro anti-tumor experiments demonstrated that the nanoparticles had a higher inhibitory activity against tumor cell proliferation compare with monomers [45]. Metal polyphenol networks were also applied in the treatment of gliomas in the brain. Epigallocatechin-3-gallate (EGCG) was first synthesized with HA to form HA-EGCG, and then EGCG was coordinated with Fe³⁺ to prepare a metal-tea polyphenol network targeting delivery of DOX for CDT combined CT of glioma [46].

Fig. 3.

Some representative natural products coordinated with Fe^3+/2+. a Carrier-free nanoparticles composed of Fe³⁺ coordinated with ART amplify therapeutic strategies for oxidative stress and MRI/FI function.

Copyright 2021, Elsevier. b Formation of nanoparticles by shikonin and Fe³⁺ through coordination-induced self-assembly for combined CT/CDT as well as MRI. Copyright 2021, Elsevier. c The synthesis, mechanism, treatment and bioimaging of EGCG-coordination Fe³⁺ loaded L-Arg. Copyright 2023, Wiley. d Fe³⁺-coordinated croconaine nanoparticle encapsulated with bovine serum albumin was designed for combined PTT and ferroptosis. Copyright 2022, German Chemical Society

Numerous studies have demonstrated that shikonin suppressed tumor growth in a variety of ways. Shikonin and Fe³⁺ were formed into spherical homogeneous nanoparticles by coordination-induced self-assembly and wrapped with polyethylene glycol and tumor-targeting moieties to achieve tumor-targeted release (GSH response). Elevated Fe²⁺ levels, GSH depletion, inhibition of GPX4 expression and increased reactive oxygen species induce lipid peroxidation, which led to the onset of ferroptosis. At the same time, the release of shikonin would amplify the degree of intracellular oxidative stress and accelerated tumor cell death through necrotic apoptosis. Additionally, the nanoparticles could be applied to MRI in vivo (Fig. 3b) [47]. This nanoplatform further proved the coordination of natural products and metal ions was an effective strategy for tumor therapy. Similarly, external loading of glucose oxidase and internal loading of the iron apoptosis inducer sorafenib after the coordination of shikonin and Fe³⁺ could lead to ferroptosis [48]. Yu et al. designed a nanoplatform with pH response via green tea polyphenol/iron complex wrapped docetaxel and cynomorium songaricum polysaccharide. The nanoplatform not only showed a favorable PTT effect, but also induced a powerful ICD and promoted an immune response. It was demonstrated that this nanoplatform could inhibit tumor metastasis and recurrence [49].

In another study, GA, 5-fluorouracil and Fe³⁺, were self-assembled to form GF-Fe NPs based on a polyphenol coordination self-assembly strategy. The GF-Fe NPs encountered cleavage by synthetic desferrioxamine, then GA and 5-fluorouracil were progressively released while the PA signals were attenuated. Real-time accurate quantitative control of drug release in real time guided by PA imaging was achieved by linear fitting between PA signal intensity and the amount of drug release [50]. Modulation of the immune microenvironment to enhance the therapeutic efficacy of tumors yielded fruitful results as well. A well-compatible (pH-responsive) metal-immunopeptide nanocomplex consists of non-covalent interactions between APP (APP is anti-programmed death ligand-1 peptide)-SPM-dextran (DEX) and sodium tripolyphosphate (TPP) as well as coordination between Fe³⁺ and TPP. This complex could generate ROS to induce oxidative stress in tumors, leading to mitochondrial dysfunction, triggering ferroptosis. The protein expression of FSP1 and GPX4 was significantly reduced and that of ACSL4 was increased in App-Fe nanocomplex-treated cells, demonstrating that it induced the occurrence of ferroptosis in the cells. Moreover, the release of DAMPs remodeled the TME and enhanced the therapeutic effect of the treatment of tumor [51]. Currently, nitric oxide (NO) was considered as enhancing the therapeutic effects of PTT and PDT on tumors. Therefore, Shi et al. constructed a new strategy, which based on EGCG and Fe3 + coordination to load the NO donor L-arginine (L-Arg) and Ce6 for synergistic PDT/gaseous/PTT (Fig. 3c) [52]. Also using EGCG, in recently published research in June 2024, Li et al. constructed a yeast microcapsule-carrying potent reactive oxygen modulator that can be used as a novel oral drug delivery system targeting the colon. This was done by encapsulating curcumin in a self-assembled manner into a metal-polyphenol network formed by the complexation of EGCG with Fe³⁺, and then using yeast microcapsules for piggybacking, which cleverly repaired the intestinal microenvironment through the triple pathway of antioxidant, inhibition of inflammation, and regulation of intestinal flora [53]. In addition, Deng et al. also constructed a metal polyphenol network (MPN) using Fe³⁺ and EGCG and loaded CeOx antioxidant nanoenzymes into it to form MPN@CeOx complex nanomaterials. This nanocomposite has excellent targeting as well as MRI functionality. EGCG and CeOx nanoenzymes together scavenge ROS, conferring anti-inflammatory and antioxidant roles to MPN@CeOx, which provides a new strategy of research for the integrated study of the diagnosis and treatment of colonic inflammation [54].

In one study, Fe³⁺-coordinated croconaine nanoparticle encapsulated with bovine serum albumin (Cro-Fe@BSA) was designed for combined photothermal and ferroptosis cancer therapy. Fe³⁺were reduced to Fe²⁺ in TME with lower pH and higher GSH concentrations. At the same time, croconaine was released and dispalyed photothermal properties under near infrared irradiation. Elevated temperature increased the rate of the Fenton reaction, leading to enhanced free radical formation. The formation of free radicals in turn prevented the formation of heat-induced heat shock proteins, thereby blocking the self-protection mechanism of cancer cells against heat. It worth notice that the activatable PAI and MRI properties of Cro-Fe@BSA NPs enable the cancer treatment safer and more reliable (Fig. 3d) [55].

Besides the above-mentioned natural products, there were several other components that coordinated with Fe³⁺ and featured multi-pathway therapeutics and multi-modal imaging as well. For example, quercetin [56], cinnamaldehyde [57], gossypol [58], Small interfering RNA (SiRNA) [59], were able to coordinate with Fe^3+/2+. Representative natural products coordinated with Fe^3+/2+ were summarized in Table 2.

Table 2.

Representative natural products coordinated with Fe^2+/3+

NO	Natural Products	Metal ions	Preparation	TME Response	Size	Treatment	Bioimaging	Reference
1	Dopamine, DA	Fe3+	Mixing	pH, GSH	204 nm	CT/CDT/PTT	——	[39]
2	Tannic acid, TA	Fe3+	–	pH	95.6 nm	CT/PTT	MRI	[33]
3	Tannic acid, TA	Fe3+	Stirring and Ultrasound	pH, ATP	121.17 nm	CT/PTT	PAI/MRI/PTI	[32]
4	Tannic acid, TA	Fe3+	–	ATP	257 nm	CDT/CT	PAI/FI	[35]
5	Tannic acid, TA	Fe3+	–	NIR	> 200 nm	PTT	MRI/PTI	[31]
6	Ellagic acid, EA	Fe3+	Magnetic stirring	TME	25 nm	PTT	PAI/MRI	[38]
7	Porphyrin	Fe3+	Stirring	pH, GSH	145 ± 20 nm	CDT/PDT	FI/MRI	[41]
8	Hematoporphyrin monomethyl ether, HMME	Fe3+	Magnetic stirring	pH, US	~ 70 nm	CT	MRI	[42]
9	Gallic acid, GA	Fe3+	–	pH	110 nm	CT/PTT	MRI	[36]
10	Artemisinin, ART	Fe3+	Magnetic stirring	pH, GSH	80 ± 8.9 nm	CT/CDT	MRI	[44]
11	Tartaric acid, TA	Fe3+	Magnetic stirring	pH	~ 125 nm	CDT/PTT	PTI	[60]
12	Tannic acid, TA	Fe3+	–	–	260.13 ± 1.86 nm	PTT/ICD	PTI	[34]
13	Tannic acid, TA	Fe3+	–	pH, ATP	< 500 nm	CT/PTT	–	[61]
14	Tannic acid, TA	Fe2+	–	pH	–	CT	–	[45]
15	Doxorubicin, DOX	Fe3+	–	pH	–	CT	–	[15]
16	Gallic acid, GA	Fe3+	–	pH	200 nm	CT/CDT	MRI/PTI	[37]
17	Baicalein	Fe2+	Stirring	——	160 nm	CDT/PTT	–	[62]
18	Epigallocatechin-3-gallate, EGCG	Fe3+	Magnetic stirring	pH	~ 100 nm	CT/CDT	FI/MRI	[46]
19	Gallic acid, GA	Fe3+	——	pH	200 nm	CT/CDT	–	[63]
20	Dopamine, DA	Fe3+	Magnetic stirring	pH	60 nm	PTT	PAI/PTI	[40]
21	Pemetrexed, PEM; pseudolaric acid B, PAB	Fe3+	Coordination-driven co-assembly	pH	100 nm	CT	MRI/FLI	[43]
22	Shikonin	Fe3+	Magnetic stirring	GSH	48.2 ± 5.4 nm	CT/CDT	MRI	[47]
23	Quercetin, QU; methotrexate, MTX	Fe3+	Magnetic stirring	pH	181 ± 2 nm	ICD/CT	FI	[56]
24	Gallic acid, GA	Fe2+	–	pH	210.1 nm	CT/CDT	FI	[64]
25	Hematoxylin, HMT	Fe3+	In vivo self-assembly	–	–	PTT/ICD	PTI	[65]
26	SiRNA	Fe2+	Quick ultrasonic	pH	180 nm	CT/CDT	MRI	[59]
27	Polyaminopyrrole, Py-NH2	Fe3+	Magnetic stirring	TME	54.3 nm	PTT	PAI/MRI	[66]
28	GAPDH SiRNA	Fe2+	Magnetic stirring	–	–	CDT	FI	[67]
29	Tannic acid, TA	Fe3+	Magnetic stirring	pH	45.0 nm	CT/CDT/IT	MRI	[68]
30	Benzoic acid, TCPP	Fe3+	Stirring	–	245.2 ± 11.2, 58.1 ± 4.8 nm	PDT/CDT	——	[69]
31	Green tea polyphenols, GTP	Fe3+	Ultrasonic	pH	274 nm	CT/PTT/IT	——	[49]
32	Croconaine	Fe3+	——	GSH/pH	91.3 ± 10.4 nm	PTT/CDT	PAI/PTI	[55]
33	Doxorubicin, DOX	Fe2+	Magnetic stirring	pH/H2O2	∼110 nm	CT/CDT/ICD	FI	[70]
34	Cinnamaldehyde, CA; DOX	Fe3+	Magnetic stirring	pH/H2O2	~ 100 nm	CT/CDT	–	[57]
35	Doxorubicin, DOX	Fe3+	Magnetic stirring	pH	77.3 ± 5.3 nm	CT	–	[71]
36	Hyaluronic acid, HA	Fe3+	Magnetic stirring	pH	225 nm	PTT	PAI	[72]
37	Artemisinin, ART; TiO2	Fe3+	Magnetic stirring	——	170 ± 20 nm	SDT/CDT	–	[73]
38	Amino acids	Fe3+	——	TME	100–140 nm		–	[74]
39	Gallic acid, GA; 5-fluorouracil	Fe3+	Magnetic stirring	DFO	139 nm	CT/PTT	PAI/PTI	[50]
40	Epigallocatechin gallate, EGCG	Fe3+	Magnetic stirring	pH	123.7 nm	PTT/CDT/CT	FI	[75]
41	Epigallocatechin gallate, EGCG	Fe3+	Magnetic stirring	TME	240 nm	PTT/PDT/	FI/PTI	[52]
42	Tannic acid, TA	Fe3+	Magnetic stirring; Ultrasonic	pH	200 nm	CDT/ICD	FI	[76]
43	Polydopamine, PDA	Fe3+	Magnetic stirring	hyperthermia/pH	129.1 ± 6.6 nm	CDT/PTT	FI/PTI	[77]
44	DNAzyme	Fe3+	Vortex	pH	200 nm	CDT/CT	FI	[78]
45	Gossypol	Fe3+	Solvothermal Decomposition	pH/laser	~ 60 nm	CT/PTT	FI/MRI	[58]
46	Lenvatinib, Adriamycin	Fe3+	–	pH	121 ± 3.74 nm	CT/ICD	FI	[79]
47	Apigenin	Fe3+	Magnetic stirring	pH/GSH	264.7 ± 56.2 nm		FI/MRI	[80]

Natural product-coordinated Cu^+/2+ self-assembly

Copper is an essential micronutrient that exists in the body mainly in the form of copper-protein complexes, which are involved in a wide range of fundamental biological processes. Copper acts as a key catalytic cofactor in a wide range of biological processes, including mitochondrial respiration, oxidative stress, and synthesis of biological compounds. Cu-coordinated compounds have promising applications as potential therapeutic agents [81].

Paclitaxel (PTX) and DOX have been widely used in the clinical treatment of tumors, and Cu²⁺ could be introduced to coordinate with them to achieve better therapeutic effects. As early as the 1980s, it was demonstrated that Cu²⁺ could coordinate with DOX, the Cu-DOX complex could induce tumor cell death by generating ROS, damaging DNA strands, and lipid peroxidation [82]. Zheng et al. prepared a GSH-responsive nanomedicine (COMBO) by coordinating Cu²⁺ with Morusin and DOX through coordination and π-π stacking effects. Their design was that the released Morusin induced paraptosis when COMBO reached the tumor site, while DOX also exerted caspase apoptotic pathway chemotherapeutic effects. To make it easier for the nanomedicine to enter the tumor cells, they synthesized COMBO with an average particle size of 97.85 nm and a uniform dispersion. The different optical phenomena produced by the coordination of Cu²⁺ with Morusin and DOX proved that the coordination was successful, they also demonstrated that the coordination-assembled nanoparticles exhibited higher tumor cytotoxicity and biosafety by cell proliferation and toxicity analysis and Hematoxylin and Eosin stains. This strategy achieved the purpose of paraptosis/CT combination for tumor treatment and effectively overcame tumor resistance [83].

Besides DOX, there were other chemotherapeutic agents that could be coordinated with Cu²⁺ to achieve antitumor effects. Chen et al. chose a widely used proteasome inhibitor ixazomib (IXZ) as ligand to coordinate with Cu²⁺, then encapsulated Disulfiram (DSF) to form the nano-formulation, which had excellent biosafety and anti-tumor effects [84]. Axitinib (AXB) is an anti-tumour drug commonly used in renal cell carcinoma, Ji et al. constructed Cu-AXB NPs by simple steps such as stirring and dialysis. Specifically, the amino, carbonyl, and sulphur groups in the AXB structure could form coordination bonds with Cu²⁺ to mediate the self-assembly of the nanoparticles, and the nanoparticles were activated and released by acidic pH after reaching the tumour site, combined with CT /CDT for the treatment of aggressive cancers (Fig. 4a) [85]. In addition, Cu²⁺ could also drive the assembly of broad-spectrum chemical drug 5-hydroxy-p-naphthoquinone (HND) and Evans Blue (EB) into nanoparticles. The EB not only stabilizes the nanoparticles but also acts as a tracer for fluorescence imaging. After reaching the tumor site, the acidic microenvironment and endogenous GSH can rupture the nanoparticles to release the drug, in which Cu²⁺ reacts with endogenous GSH and H₂O₂ to generate ROS, and HND not only exerts the effect of chemotherapy, but also amplifies the endogenous H₂O₂ through intracellular oxidoreductase to amplify the oxidative stress in a cascade on-demand together with Cu²⁺ (Fig. 4b) [86].

Fig. 4.

Some representative natural products coordinated with Cu²⁺. a) Methods of Axitinib coordination with Cu²⁺, response to acidic pH release, and treatment strategies.

Copyright 2023, Royal Society of Chemistry. b) Coordination of Cu²⁺ with EB/HND and TME responsive release. Copyright 2023, Royal Society of Chemistry. c) CuS NDs assembled by PVP and combined with DDTC to achieve a combined CT/PDT/PTT strategy and PAI/PTI functions. Copyright 2020, American Chemical Society. d) Cu²⁺-driven coordination and assembly aggregation of DOX and DA to achieve CDT/PTT and PAI functions. Copyright 2022, Ivyspring International Publisher

Huang et al. developed a novel diethyldithiocarbamate (DDTC) nanoparticle loaded with ultrasmall CuS nanodots (CuS NDs), which is triggered by laser to release Cu²⁺, and has photothermal and ROS-generating functions, synergizing the chemotherapeutic effects of DDTC to jointly fight tumours. Meanwhile, this nanoparticle also has the function of photoacoustic imaging, which provides a guidance for its application (Fig. 4c) [87]. Guo et al. reported the synergistic PDT/CDT/CT triple therapy effect of mesoporous silica nanoparticles (MSNs) delivering methylene blue (MB) and DOX, the outermost layer of MSNs achieves pH-responsive release by coordination with Cu²⁺ and immobilization with DOX to achieve CDT and CT. Combining all three treatment modalities for tumors provides favorable results for cutaneous melanoma [88]. Xiong et al. synthesized a TME-activated nanoplatform using a one-pot method, where hydroxyethyl starch prodrug (HES-SS-DOX) and DA were coordinated and aggregated into nanoparticles via Cu²⁺, in which Cu²⁺ acted as a bridge to connect DA and DOX. After reaching the tumor site and cleavage, DOX exerted CT, while Cu²⁺ acted as CDT, and the coordination and aggregation makes the near-infrared absorption of PDA significantly enhanced, which strengthen the PTT effect (Fig. 4d) [89].

CDT, which uses Fenton action catalysts to kill cancer cells by converting intracellular H₂O₂ into toxic ·OH, has a promising application in tumor therapy. Among the various metal-mediated Fenton-like reactions, those involving Cu^+/2+ showed higher reaction rates than other metal ions under weakly acidic conditions. Theoretically, the Fenton catalytic efficiency of Cu-based nanoplatforms is about 160 times higher than that of conventional iron-based reagents. An efficient hierarchical structured nanoplatform with transferrin-labeled Cu-oxide dot-decorated Cu@Gd₂O₃ was designed to act as a GPX4 antagonist and a SOD-1 agonist, leading to intracellular ROS and H₂O₂ accumulation. Self-supply of Cu⁺ was achieved by utilizing the ratio of CuO to elemental Cu nuclei, which catalyzed the formation of ·OH from H₂O₂ [90]. CDT is difficult to achieve favorable results if it only relies on endogenous H₂O₂ in tumor cells. A therapeutic strategy that could simultaneously inhibit enzyme activity and amplify CDT was proposed: a thioglycolic acid (TGA)-Cu coordinated nanoparticle with a fast response to GSH was synthesized to enhance CDT efficiency, at the same time the oxidized glutathione (GSSG)-Cu complex triggered oxidative stress of H₂O₂ to prompted tumor cell death [91]. Multi-modality combination therapy alleviates the drawbacks of monotherapy and demonstrates better treatment effects. For example, hollow mesoporous silica nanoparticles (HMSNs) were utilized as carriers and loaded with the complexes of Cu²⁺ and PDA to form nanoparticles. Among them, the photothermal performance of PDA was further improved by its coordination with Cu²⁺; the temperature increase induced by PTT further increased the CDT efficiency, thus realizing the synergistic effect of the two modes of PTT/CDT [92]. Similarly, Liu et al. used a Cu²⁺-triggered coordination strategy to assemble Cu²⁺ and Indocyanine Green (ICG) with tirapazamine (TPZ) to form Cu-ICG/TPZ NPs. The Cu-ICG/TPZ NPs would aggregate at the tumor site through the enhanced permeability and retention (EPR) effect. The hypoxia of the TME would trigger the CT effect of the TPZ, Cu²⁺ and ICG would play the roles of CDT and PDT, respectively, resulting in a synergy with the Synergistic tumor therapy with three therapeutic modalities [93].

Flavonoids and polyphenols due to their benzene ring and the oxygen atom on the carbonyl group to form a large π-bond conjugate system, the oxygen atom of the carbonyl group in the C ring has a strong coordination ability. It can be coordinated with ions of trace metal elements to form stable flavonoid complexes, such as TA, curcumin and cardamonin that have been coordinated with Cu²⁺ for the treatment of tumors. For example, Sun et al. coordinated Cu²⁺ with TA then encapsulated by phycocyanin (PC), Zn²⁺, disulfide-bonded cross-linking agent and HA to constitute stable flavonoid composite nanocapsules (PZTC/SS/HA). The principle of their experiment was that the PZTC/SS/HA could be activated by TME to cleave and release Cu²⁺, followed generation of Cu²⁺ sulfide (CuS) for PTT by endogenous H₂S-triggered. In addition, PTT and Cu²⁺ could activate and enhance CDT. To demonstrate the pH/GSH response of PZTC/SS/HA, the results in different solutions show that the PZTC/SS/HA collapsed the most completely and released Cu²⁺ faster in the acidic environment and the simultaneous presence of GSH. The prepared PZTC/SS/HA showed concentration- and power-dependent photothermal effects under 1064 nm laser irradiation. Their TME-activated synergistic PTT/CDT strategy showed promising therapeutic effects, opened new avenues for the generation of novel nano-agents and effective TME-responsive synergistic treatment of cancer [94]. Cardamonin is a polyphenolic natural product that is cytotoxic to a variety of cancer cells. It has been reported that the complex formed by Cu²⁺ and cardamonin could induce apoptosis in cancer cells by inducing DNA damage and generating ROS, its biological activity was verified on MDA-MB-468 and PANC-1 cells [95]. Naringenin is a widely distributed flavonoid compound with antioxidant and antitumor effects. The formation of a triple component complex with Cu²⁺ and naringenin (Nar) using bartophenanthroline as a ligand showed high selectivity and toxicity against A549 cells [96]. Emami et al. synthesized a Cu²⁺ complex of curcumin and 2,2'-bipyridine-5,5'-dicarboxylic acid, which was highly cytotoxic to the cancer cell line MDA-MB-231 and safe for normal cells [97]. Cu²⁺ was coordinated with shikonin then added DTC-PPB to become NPs, the NPs could be cleaved by ROS, the released DTC rapidly chelate Cu²⁺ to synthesize highly cytotoxic Cu(DTC)₂ and induce the release of DTC-PPB, which in turn ROS could be generated to release a positive feedback activation loop to further activation. Thus, this nano-amplifier could be triggered by ROS in the TME to develop a cascade-amplified positive feedback loop in-situ to enhance the therapeutic efficacy of tumor treatment [98].

Also utilizing the TME response, Zhu et al. designed a self-delivery nanomedicine assembled from Cu²⁺ coordination-driven celastrol and ICG. The nanomedicine were wrapped with red blood cell membranes (RBCs) to prolong the drug's circulation time and activated by GSH in TME to exert the combined therapeutic effect of CT/PTT/CDT [99]. Similarly, a Cu²⁺-coordinated nano-formulation utilizes Cu²⁺ to drive the assembly of the photothermite ICG and the photodynamic agent pheophorbide A (PhA). It could be decomposed by acidic pH and high GSH in TME, then Cu²⁺ could consume GSH to catalyze ROS production. Meanwhile, after fluorescence and photoacoustic imaging-guided NIR irradiation given at different wavelengths, ICG and PhA played the roles of PTT and PDT, respectively, to induce apoptosis of tumor cells (Fig. 5a) [100]. Likewise, a hydrogel composed Cu²⁺ with ICG and HA could also function as a PTT/CDT under NIR [101]. Cu²⁺ also could be assembled with cy series dyes in a coordination-driven manner, followed by encapsulation with HA to form nanoparticles with synergistic PTT/CDT dual therapeutic modes. A strong anti-tumor effects could be achieved at low doses [102].

Fig. 5.

Some representative natural products coordinated with Cu²⁺. a Cu²⁺ with ICG and PhA via coordination for PDT/PTT combination and PAI/FI combination.

Copyright 2021, Elsevier. b Cu²⁺, DOX, and NLG919 self-assembly for ICD and MRI. Copyright 2021, Elsevier. c Cu²⁺-mediated self-assembly of glycyrrhizic acid and NCTD into carrier-free natural injectable small-molecule hydrogels activates CDT/CT/Cuproptososis via NIR. Copyright 2023, Elsevier. d Cu²⁺ coordinated regorafenib and encapsulated with H-ferritin (HFn) to obtain brain-targeted nanoparticles for synergistic treatment of glioblastoma. Copyright 2023, Wiley

In addition to common therapeutic modalities such as PTT/CDT/CT, immunogenic cell death (ICD) was also a popular research topic. Cu²⁺, DOX, and NLG919 could self-assemble by coordination through π-π stacking effect to form a nanoscale oxidative stress amplifier (called Cu-DON). It could effectively aggregate at the tumor area, release DOX under GSH to initiate immunogenic chemotherapy (IC). Meanwhile, Cu²⁺-triggered oxidative stress enhancement disrupted the intracellular redox homeostasis, leading to ICD. Dual immunotherapy effectively inhibited the growth of primary and distal tumors, providing a new direction for clinically blocking tumor growth and metastasis (Fig. 5b) [103]. Cu²⁺ was coordinated with linoleic acid hydroperoxide (LAHP) to synthesize NPs, the NPs were brought to the tumor site with R7-modified iRGD peptide. Under the acidic pH of TME, the decomposition into LAHP and Cu²⁺ produced ROS and further induced ICD [104]. Wang et al. constructed a mixed-valent Cu²⁺ coordination nanopolymer: 5'-guanosine monophosphate (5'-GMP), which is widely present in organs, and then self-assembled into Cu-NCPs with a particle size of about 100 nm. The valence state jump of the coordinated, partial conversion of Cu²⁺ to Cu⁺ enhanced RT-mediated oxidative stress, which in turn induced the release of potent ICD and tumor-associated antigens and DAMPs. Cu-NCPs significantly facilitated T-cell infiltration, thereby enhancing the radioimmunotherapy of in situ and metastatic tumors [105]. Accumulation of intracellular Cu^+/2+ triggers aggregation of mitochondrial lipidated proteins and destabilization of Fe-S cluster proteins, leading to a novel type of regulated cell death distinct from oxidative stress-associated cell deaths (e.g., apoptosis, Ferroptosis and necrotic apoptosis), called Cuproptosis [106]. A Cu²⁺-mediated self-assembly of glycyrrhizic acid and nortriptyline (NCTD) into a carrier-free natural small-molecule water gel-for-injection by coordination and hydrogen bonding. It could consume GSH to generate ROS under NIR and synergistically regulate TME through apoptosis, CDT, Cuproptosis and anti-inflammation. The gel composition is the active component of traditional Chinese medicine, the preparation process was simple. The carrier-free protein drug generated by the coordination of natural products with Cu^+/2+ has a brilliant prospect of application in the treatment of tumors (Fig. 5c) [107]. Jia et al. incubated Cu²⁺ with regorafenib for 20 min and then added H-ferritin (HFn) and stirred for 24 h to obtain brain targeted nanoparticles. HFn as a TfR1 targeting agent, could reach the glioblastoma site and release regorafenib in response to acidic pH, leading to cellular autophagy. In addition, the increase of intracellular Cu²⁺ played a role in Cuproptosis, CT/Cuproptosis synergistically treats glioblastoma (Fig. 5d) [108].

Metal–organic complexes (MOCs) or metal–organic frameworks (MOFs) possess a great deal of attraction in nanodrug delivery systems for tumors. As an emerging porous material with organic–inorganic hybridisation, MOFs have high specific surface area and porosity compared with traditional drug delivery systems, which is conducive to effective encapsulation and delivery of various drugs. Their toxicity can also be regulated by selecting suitable metal ions, so that MOFs have sufficient stability and low biotoxicity in organisms [109, 110]. They have been applied in energy storage, catalysis, sensing, bio-imaging, drug delivery and so on [111, 112]. Metal ions coordination-driven composite systems enabled stable delivery of specific drugs in response to physiological conditions. Li et al. utilized the metal-coordination interaction of Cu²⁺ with PPEIDA and DOX to construct a pH-sensitive nanoparticles. Its excellent targeting and pH sensitivity enabled real-time monitoring of drug loading and release [113]. A highly efficient mitochondria-targeted photosensitizers with aggregation-induced release (AIE) characteristics for effective PDT by using a Cu²⁺-based metal–organic framework MOF-199 was synthesized, it showed excellent mitochondri-targeting ability and specific ablation of cancer cells under NIR irradiation [114]. A dual-loaded nanodrug based on metal–organic particles with Cu²⁺ as a ligand bridge connecting Combretastatin A4 (CA4) and Mitoxantrone (MIT) to obtain CMMOP. CMMOP was relatively stable under normal physiological conditions and cleaves under the acidic pH of tumors to release the drug, providing good performance for precision therapy [115].

In addition to inorganic Cu^+/2+, Copper oxide nanoparticles and organic forms of Cu^+/2+ complexes could also be used to synthesize cytotoxic anticancer drugs, leading to irreversible membrane damage and cell death. For example, the combination of CuO NPs with N-acetylcysteine generates ROS while interfering with the cell membrane and caspase-independent cell death [116]. An emerging therapeutic approach for CO gas therapy has been extensively investigated. Sun et al. used a coordination assembly strategy to synthesize Cu²⁺-flavonoid coordination polymer nanopredrug. This nanopredrug was relatively stable, when it reached the tumor site, a large quantity of GSH in the TME would break the coordination bond, causing the release of Cu⁺ and free Fle. Cu⁺ was used to react with H₂O₂ to exert CDT; NIR breaks the C–C bond and releases CO to exert gas therapy [117]. Representative natural products coordinated with Cu^+/2+ were shown in Table 3.

Table 3.

Representative natural products coordinated with Cu^+/2+

NO	Natural products	Metal ions	Preparation	TME Response		Size	Treatment	Bioimaging	Reference
1	Diethyldithiocarbamate, DDTC	Cu2+	Stirring	NIR		~ 8.8 nm	PTT/PDT/CT	PAI/PTI	[87]
2	Paclitaxel, doxorubicin	Cu2+	Thin-film hydration method	ROS/GSH		128.5 ± 2.610 nm	CDT/CT	–	[118]
3	Indocyanine green, ICG; pheophorbide A, PhA	Cu2+	Stirring	pH/GSH/NIR		~ 141.6 nm	PTT/PDT/CDT	FI/PAI/PTI	[100]
4	Indocyanine green, ICG; hyaluronic acid, HA	Cu2+	Stirring	pH		–	PTT/CDT	PTI/FI	[101]
5	Cardamonin	Cu2+	–	–		–	CT/CDT	–	[95]
6	poly(p-phenylene ethynylene) backbone and iminodiacetic acid (IDA), PPEIDA; DOX	Cu2+	Stirring	pH		~ 171.7 nm	CT	–	[113]
7	Hyaluronic acid, HA; fluorescence dye, Cy	Cu2+	Stirring	GSH		~ 100 nm	CDT/PTT	FI/PTI	[102]
8	3-hydroxy-4’-carboxyl flavone (Fle)	Cu2+	Sonicated	NIR/GSH		~ 150 nm,	CO/CDT	–	[117]
9	N-acetylcysteine	Cu2+	–	–		~ 80 nm	CT	–	[116]
10	5′-guanosine monophosphate, 5'-GMP	Cu2+	Stirring	Ionizing radiation		100 ± 7.48 nm	radioimmunotherapy/CDT	–	[105]
11	Apoferritin	Cu2+	Stirring	pH		~ 20 nm	Autophagy-dependent apoptosis, CT	–	[119]
12	Polydopamine, PDA	Cu2+	Magnetic stirring	NIR		~ 130 nm	CDT/PTT	–	[92]
13	Doxorubicin, NLG919	Cu2+	Magnetic stirring			139.3 ± 0.6 nm	ICD/CDT	MRI	[103]
14	Morusin; Doxorubicin, DOX	Cu2+	Mixed centrifugal resuspension	GSH		97.85 ± 0.42 nm	PCD/CT	–	[83]
15	Naringenin, Nar	Cu2+	–	–		–	CDT/CT	–	[96]
16	Thioglycolic acid, TGA	Cu2+	self-assemble	GSH		~ 43.8 nm	CDT	–	[91]
17	Ixazomib, IXZ	Cu2+	Reversed-phase microemulsion method, stirring	GSH		–	CT	FI	[84]
18	Curcumin,Cur; 2,2'-bipyridine-5,5'-dicarboxylic acid, BPYD	Cu2+	–	–		–	CT	–	[97]
19	Doxorubicin, DOX	Cu2+	Stirring	pH, NIR		~ 100 nm	PDT/CDT/CT	–	[88]
20	Phosphorus dendrimer-copper (II) complexes (1G (3) -Cu)	Cu2+	Stirring	TME		~ 210 nm	ICD/CT	MRI	[120]
21	Shikonin	Cu2+	Stirring	ROS		~ 120 nm	CT	FI	[98]
22	Tirapazamine; ICG	Cu2+	Ultrasound, Stirring, dialysis	GSH, Hypoxia		~ 150 nm	CT/CDT/PDT	FI/PTI	[93]
23	Amphiphilic amino acids; glucose oxidase, GOx; doxorubicin, DOX; camptothecin, CPT	Cu2+	–	TME		–	CT/CDT	–	[121]
24	Linoleic acid hydroperoxide, LAHP	Cu2+	Stirring	pH		~ 100 nm	PDT/ICD	–	[104]
25	Combretastatin A4, CA4; mitoxantrone, MIT	Cu2+	–	pH		–	CT	–	[115]
26	Dopamine, DA	Cu2+	Stirring	TME		~ 171.2 nm	CDT/CT/PTT	PAI/PTI	[89]
27	Celastrol, CST; ICG	Cu2+	Stirring	GSH		~ 110 nm	CDT/CT/PTT	PTI	[99]
28	Disulfiram, DSF; mitoxantrone, MTO	Cu2+	Stirring, ultrasonically disperse	pH		~ 110 nm	CT/CDT	–	[122]
29	Gallic acid, GA	Cu2+	Stirring, hydration	GSH		~ 50 nm	PTT/CDT	PTI	[123]
30	Tannic acid, TA	Cu2+	Magnetic stirring	TME		~ 133.5 nm	PTT/CDT	PTI	[94]
31	Glycyrrhizic acid, GA; norcantharidin, NCTD	Cu2+	Magnetic stirring	NIR		–	CDT/CT/cuproptosis	FI	[107]
32	Human H-ferritin	Cu2+	Magnetic stirring	pH		~ 15.5 nm	cuproptosis/CT	FI	[108]
33	L-cysteine; polyvinylpyrrolidone, PVP	Cu2+	Stirring	pH		~ 100 nm	CDT/CT	–	[124]
34	Zinc protoporphyrin IX, ZnPPIX	Cu2+	ultrasound-assisted synthesis; Stirring	GSH		178 nm*60 nm	CDT/CT	–	[125]
35	Histidines in ARGD polypeptide	Cu2+	chelation	TME		~ 60 nm	CT/CDT	FI	[126]
36	Dopamine, DA	Cu2+	Magnetic stirring	pH		~ 100 nm	CDT/PTT/CT	PAI/PTI	[127]
37	Gum Arabic, GA	Cu2+	Magnetic stirring and shaken in a rotating incubator	pH/GSH		~ 92.17 nm	CT/CDT	–	[16]
38	Apatinib	Cu2+	–	TME		–	CT/CDT	–	[128]
39	Axitinib	Cu2+	Stirring; dialysis	pH		~ 180 nm	CT/CDT	FI	[85]
40	Evans Blue, EB; 5-hydroxy-p-naphthoquinone, HND	Cu2+	shaking	TME		~ 200 nm	CDT/CT	FI	[86]
41	Zinc phosphate, ZnP; prussian blue, PB	Cu2+	Stirring	pH		~ 160 nm	CDT/PTT/CT	PTI	[129]
42	Cinnamaldehyde	Cu2+	–		white LED light irradiation		CDT	–	[130]

Natural product-coordinated Mn^2+/3+ self-assembly

Mn^2+/3+ is an essential trace element for living organisms and distributed in various tissues and body fluids. It plays a positive role in the growth and development of bones and the improvement of muscle hematopoiesis. In addition, Mn^2+/3+ can promote the survival and proliferation of immune T-cells and effectively propel the tumor-killing ability of NK cells [131, 132]. Currently, extensive research showed that natural products coordinated with Mn^2+/3+ would offer an excellent PTT, CDT and immune effect. They could be also utilized for PAI, MRI and PTI due to the paramagnetic properties [133, 134].

Immunotherapy has emerged as an effective strategy for the treatment of cancer. Numerous studies have reported Mn^2+/3+-mediated immune responses [135]. In this aspect, Geng et al. self-assembled Mn²⁺ with DOX and Ce6 into highly drug-loaded nanoparticles, which were further encapsulated with erythrocyte membranes to improve the dispersion and stability of the nanoparticles. It indicated that the encapsulated nanoparticles enhanced the anti-tumor response of primary and distant tumors, providing a new approach for immunotherapy (Fig. 6a) [136]. Liu et al. reported an innovative strategy for inhibiting heat shock proteins to improve PTT efficiency: GA and Mn²⁺ coordinated through stirring to form nanoparticles. Degradation under acidic conditions releases Mn²⁺and GA, leading to upregulation of ROS, mitochondrial dysfunction, and pyroptosis. The reduction of ATP and accumulation of ROS during this process provide a powerful method for inhibiting heat shock proteins expression, making it possible for mild PTT mediated by nanomaterials (Fig. 6b) [137]. In addition, Yan et al. reported a nanoplatform via Mn²⁺ coordinated and self-assembled with CDN STING, which effectively delivered STING agonists to immune cells [138]. The amphiphilic PEG-polyphenol was successfully utilized to coordinate with NaGdF₄ and Mn²⁺. This radiosensitizer increased the sensitivity of tumor cells to X-rays and promoted immune cell maturation. In addition, Mn²⁺ could promote STING pathway activation, and the combination of the two therapeutic modalities was interesting for tumor radiotherapy [139]. Dai et al. studied the reversal of the immunosuppressive microenvironment by self-assembling and efficiently loading immunomodulators (R848) with NIR-II semiconductor polymer dots and Mn²⁺. They skillfully assembled the function of FI, PAI, PTT and CDT in nanoparticles. In addition, the nanoparticles catalyzed the generation of ·OH from H₂O₂ leading to a decrease in the absorption peak of MB, proving that it had promising CDT effects [140].

Fig. 6.

Some representative natural products coordinated with Mn²⁺. a Mn²⁺ was self-assembled with DOX and Ce6 to form highly drug-loaded nanoparticles and then encapsulated with erythrocyte membrane for ICD.

Copyright 2021, Elsevier. b GA and Mn²⁺ were coordinated to form nanoparticles and cleaved under acidic conditions to cause CT/PTT. Copyright 2023, springer nature

The combination of gene therapy and CT provides an effective solution for tumor treatment. TA coordinated with Mn²⁺ to form a high-loading carrier for the effective co-delivery of rapamycin (RAP) and Beclin-1 to achieve inhibition of Deoxyribozyme (DNAzyme, DZ) [141]. Similarly, in another study, Mn²⁺ coordinated with TA was utilized to deliver the anticancer drug DOX and DNA enzymes with the high drug loading property. Both in vivo and in vitro studies demonstrated that nanoparticles presented satisfactory antitumor efficacy [142]. In addition, Mn²⁺-mediated imaging technology visualizes tumor therapy. Wu et al. synthesized a pH-responsive multifunctional nanoparticle based on the coordination of methotrexate (MTX) and Mn²⁺, encapsulating a nanoscale polymer of PEG, in which Mn²⁺ acted as the MRI contrast agent, MTX was as the chemotherapeutic agent, and PEG provided the nanoparticles with a stable environment, respectively. In vivo MRI indicated that nanoparticles exerted favorable anti-tumor effects [143]. Furthermore, Geng et al. designed and developed a GSH-responsive nanoparticle in which Mn³⁺ was coordinated with hematoporphyrin monomethyl ether (HMME) and then loaded with DOX, subsequently modified with a targeted polyethylene glycol polymer to enhance tumor targeting. Nanoparticles ruptured and then Mn³⁺ reduced to Mn²⁺ for PDT and MRI in a high level GSH environment, while DOX was applied for CT. In vivo anti-tumor experiments demonstrated that it significantly inhibited tumor growth and showed a favorable biosafety profile [144]. Mn²⁺ was coordinated with AsO₄³⁻ and ICG to form MnAs-ICG NPs. The chemodynamic property of Mn²⁺, the chemotherapeutic property of AsO₄³⁻, and the photothermal property of ICG were fully utilized. In the meanwhile, the presence of Mn²⁺ and ICG allowed the application of MRI and FI [145].

In vivo coordination self-assembly enhanced drug efficacy. A study utilized PEG-modified hollow mesoporous manganese dioxide nanoparticles to load with the antitumor drug bleomycin (BLM). BLM and Mn²⁺ were released in the TME with in situ coordination self-assembly. The antitumor effect of BLM was enhanced, and it could be also employed in MRI to monitor the therapeutic effects in vivo [146]. Overall, the coordination of Mn^3+/2+ with natural products effectively stimulated the immune response of the body, and demonstrated promising therapeutic effects in PTT and CDT. Meanwhile, the introduction of Mn^3+/2+ allowed for PAI, PTI and MRI. Representative natural products coordinated with Mn^2+/3+ were shown in Table 4.

Table 4.

Representative natural products coordinated with Mn^2+/3+

NO	Natural products	Metal ions	Preparation	TME Response	Size	Treatment	Bioimaging	Reference
1	Tannic acid, TA	Mn2+	Stirring	pH, GSH	151 ± 24 nm	GT/CT	FI	[141]
2	Tannic acid, TA	Mn2+	High temperature heating	pH, GSH	~ 230 nm	CDT/GT/CT	FI	[142]
3	Methotrexate, MTX	Mn2+	Sonication	pH	93.3 ± 10.3 nm	CT	MRI	[143]
4	Polydopamine, PDA	Mn2+	Magnetic stirring	–	105 nm	CDT/PTT	MRI/PTI /FI	[147]
5	Hematoporphyrin monomethyl ether, HMME	Mn3+	Mild sonication	GSH	~ 100 nm	CT/CDT/PDT	MRI	[144]
6	Doxorubicin, DOX; chlorin e6, Ce6	Mn2+	Sonication	pH	125 ± 6.1 nm	CT/PDT	MRI	[136]
7	Carrying DNA	Mn2+	–	pH	~ 100 nm	CDT	–	[148]
8	Cyclic dinucleotide, CDN	Mn2+	–	pH	118 ± 41 nm	ICD	–	[138]
9	Indocyanine green, ICG	Mn2+	Magnetic stirring	pH	144.87 ± 2.91 nm	CT/CDT/PTT	FI/MRI	[145]
10	Beomycin, BLM	Mn2+	In Vivo self-assembly	GSH	~ 300 nm	CT	MRI	[146]
11	Resiquimod R848	Mn2+	Stirring	pH	~ 100 nm	PTT/ICD/CDT	FI/PAI	[140]
12	Gallic acid, GA	Mn2+	Magnetic stirring	pH	164.2 nm	PTT	PTI	[137]
13	2-methylimidazole, 2-MI	Mn2+	Magnetic stirring	pH	~ 130 nm	ICD	FI	[135]
14	Banoxantrone; AQ4N	Mn2+	Magnetic stirring	pH	~ 100 nm	CT	PAI	[134]

Natural product-coordinated Zn²⁺ self-assembly

Zinc is existed mainly in the form of enzymes and performs an important function in promoting wound healing and bacterial inhibition. It supports coordination in different geometries as well as being able to facilitate ligand exchange [149]. Zinc derivatives are proposed as antitumor agents and numerous Zinc coordination complexes have been synthesized.

Lei et al. assembled zinc-fluorouracil metallodrug networks (Zn-Fu MNs) by one-pot coordination of zinc nitrate and fluorouracil with cleavage of the mitochondrial electron transport chain. Zn²⁺ induced ROS production and 5-fluorouracil interfered with DNA synthesis, both of which synergistically activated immunotherapy (Fig. 7a) [150]. Zn²⁺ could also drive RNA self-assembly to form spherical nanoparticles with excellent RNA loading and bioavailability. The results showed that RNA oligonucleotides with different lengths and structures could self-assemble into nanoparticles. This coordinated-induced self-assembly extended the application of RNA therapeutics (Fig. 7b) [151]. Endogenous Zn²⁺ and small biomolecules (l-cystine, Cys) were assembled into a new tumor-sensitive metal–organic complex, and then DOX was encapsulated inside. The nanomedicine was cleaved under the overexpressed GSH in the tumor to release the drug, which showed higher targeting and cytotoxicity than free DOX. Since both metal ions and organic ligands are derived from natural products, it is characterized by favorable biocompatibility, high tumor sensitivity and low toxicity for normal cells [152].

Fig. 7.

Some representative natural products coordinated with Zn²⁺. a) Self-assembly of Zn²⁺ and Fu into metallodrug networks for CT/CDT/ICD combination.

Copyright 2022, Ivyspring International Publisher. b) Schematic diagram of Zn²⁺-driven RNA self-assembly to form spherical nanoparticles. Copyright 2021, Wiley

The research and development of coordination-driven metal–organic nanoplatforms provided an effective strategy and direction for treating glioblastoma as well. Gao et al. reported an in-situ assembly nanoplatform based on RGD peptide-modified bisulfite-Zn²⁺-dipicolylamine-Arg-Gly-Asp and ultrasmall Au-ICG nanoparticles. It could target tumors and waited for ultra-small Au nanoparticles to cross the blood–brain barrier before assembling with them in situ to form a large nanocluster. In situ photothermal therapy by NIR irradiation under FI, MRI and PAI guidance [153]. In fact, mild PTT (42–45 °C) exerted a significant therapeutic effect with less tissue damage [154]. Combining gene therapy (GT) with mild PTT could inhibit the heat resistance of tumor cells, minimize side effects and improve the overall therapeutic efficacy. A nanoplatform for co-delivery of photothermal and gene therapy agents was developed by self-assembly using a one-pot method. IR780-1 and 2-methylimidazole (2-MIM) were utilized as ligands to coordinate with Zn²⁺ in the presence of siRNA to form a nanoplatform. It was available for PTI, PAI, and FI-guided PTT and GT. At the same time, it overcame the short half-life and instability of drugs in conventional PTT and GT therapy [155]. Representative natural products coordinated with Zn²⁺ were summarized in Table 5.

Table 5.

Representative natural products coordinated with Zn²⁺

NO	Natural products	Metal ions	Preparation	TME Response	Size	Treatment	Bioimaging	Reference
1	Fluorouracil	Zn2+	Ultrasound	pH/ATP	100 nm	ICD	FI	[150]
2	IR780-1, 2-methyl-imidazole, siRNA	Zn2+	Stirring	NIR	150–200 nm	PTT/GT	PTI/PAI/FI	[156]
3	RNA	Zn2+	Stirring	–	60–120 nm	CT	FI	[151]
4	L-cystine	Zn2+	Stirring	GSH	189.1 ± 3.8 nm	CT	–	[152]
5	Dipicolylamine-Arg-Gly-Asp, Au, ICG	Zn2+	In Vivo assembled	NIR	100 nm	PTT	FI/PAI/MRI	[153]

Natural product-coordinated Co³⁺ self-assembly

Cobalt is a biologically essential trace element usually found in vitamin B12 (vitamin B12, also known as cobalamin, the only vitamin containing the metal element). Its physiological functions are also shown through the actions of vitamin B12, including hematopoietic function, protein metabolism and the synthesis of certain enzymes. Co³⁺ achieved coordination assembly with some natural products for tumor therapy. For example, Co³⁺ and tetrakis (4-carboxyphenyl) porphyrin (TCPP) were assembled into a metal–organic framework (MOF) then coordinated it with mitochondria-targeted triphenylphosphonium (TPP) to construct an ultrasound-responsive nano-agonist TPP@CoTCPP. Due to the deep penetration and non-invasive nature of ultrasound, after the nanosheets entered into the tumor cells and localized in the mitochondria, the ultrasound drived the MOF to generate ROS. It resulted in a precise and controllable stimulation of the cGAS-STING pathway and promoted the immune-suppressing tumors [157]. Representative natural products coordinated with Co³⁺ were displayed in Table 6.

Table 6.

Representative natural products coordinated with Co³⁺, Mo^4+/5+, Sn⁴⁺, Ni²⁺, V^3+/4+/5+ and multiple ions

NO	Natural Products	Metal ions	Preparation	TME Response	Size	Treatment	Bioimaging	Reference
1	Tetrakis(4-carboxyphenyl) porphyrin, TCPP; triphenylphosphonium,TPP	Co3+	ultrasound	US	962.2 ± 8.739 nm, 2 nm	SDT	FI	[157]
2	Epigallocatechin gallate, EGCG	Mo5+	biomineralization	GSH	4.75 ± 0.06 nm	CDT/ICD	–	[158]
3	Polyethylene glycol, PEG	Mo4+	hydrothermal method; Stirring	–	~ 400 nm	CT	–	[172]
4	Polydopamine, PDA	Mo4+	Stirring	pH/ NIR	50–100 nm	CT/PTT	FI/PAI/MRI	[159]
5	Ferulic acid	Sn4+	–	–	–	CT	–	[160]
6	Natural bacteriochlorophyll A	Sn4+	Stirring	NIR	–	PDT/CT	–	[161]
7	Schiff base	Ni2+	–	–	–	CT	–	[173]
8	Tannic acid, TA	V5+	Magnetic stirring	pH	130 nm	PTT/CDT	PTI	[167]
9	Tannic acid, TA	V4+	Magnetic stirring	–	80 nm	PTT/ICD	–	[168]
10	Tris-catechol	V3+	Magnetic stirring	pH	231 nm	CT	–	[174]
11	Tannic acid, TA	V5+	Magnetic stirring	pH	71.8 nm	ICD/CDT	FI	[175]
12	Tannic acid, TA	Fe3+/ Mn2+	Magnetic stirring	NIR	168 nm	ICD/PTT/CDT	PTI	[169]
13	Linoleic acid hydroperoxide, LAHP	Cu2+/ Fe3+	Magnetic stirring	pH	~ 100 nm	PDT/ICD	–	[104]
14	Gossypol	Co3+/ Fe3+	Ultrasound	NIR	60 nm	CT/PTT	FI/MRI	[58]

Natural product-coordinated Mo^4+/5+ self-assembly

Molybdenum, an essential trace element for humans, animals and plants, is naturally present in multiple enzymes. Its complexes are expected to be potential candidates for biomedical applications. Zhen et al. inspired by the game theory, proposed a cancer therapy by combining CDT/ICD, considering the evolutionary, competitive and cooperative relationship between certain molecules and cancer cells. They coordinated Mo⁵⁺ with EGCG to form a nanoparticle. It eliminated the excess GSH through Michael addition reaction and regulated ROS levels through Fenton-like reactions and the Russel mechanism, thus disrupting the redox balance. Furthermore, the NPs formed aggregates in TME and mechanically disrupting endosomes and plasma membranes to induce ICD. This strategy not only generated ROS by consuming GSH with the introduction of Mo⁵⁺, but also induced ICD through competition for intracellular GSH to form larger aggregates, thus facilitating immunotherapy [158]. Yang et al. coordinated PDA with MoS₂ and targeted modification of its surface before loaded DOX to form a multifunctional nanoplatform. The nanoplatform could be monitored by FI, PAI and MRI to effectively aggregate at the tumor site and release DOX under pH/NIR triggering, and the combination therapy of PTT/CT showed excellent tumor cell killing effect [159]. Representative natural products coordinated with Mo^4+/5+ were displayed in Table 6.

Natural product-coordinated Sn⁴⁺ self-assembly

Tin plays a crucial role in the human body. It could produce anti-tumor tin compounds in the human thymus gland. Furthermore, it also could promote the synthesis of proteins and nucleic acids and affect the function of hemoglobin, etc. Sn⁴⁺ have been found to coordinate with many natural products for use in the treatment of tumors. Ferulic acid (FA) is a polyphenolic component from natural plants with antioxidant and anti-tumor effects. Pellerito et al. synthesized a new complex (ferulate (TBT-F) by coordinating tributyltin (IV) with FA. Sn⁴⁺ was at least penta-coordinated and the ligand acted as a monoanionic ligand by bridging the carboxylate anion. TBT-F possessed a significant killing effect on HCT116, HT-29 and Caco-2 colon cancer cells in a concentration range of nM, whereas FA without Sn coordination was ineffective under the same conditions [160]. Natural bacteriochlorophyll A was coordinated with Sn to form a complex with a photodynamic property to exert PDT for treating tumors [161]. Representative natural products coordinated with Sn⁴⁺were displayed in Table 6.

Natural product-coordinated Ni²⁺ self-assembly

In our daily diet, chocolate, nuts and cereals are rich in nickel, which are one of the essential trace elements and possess the ability to stimulate hematopoiesis. Hosseini et al. prepared a series of nickel SCS complexes characterized by a stable mesophenylene center and two unstable thioamides donors at the periphery of the ligand. The results demonstrated its effect on the treatment of estrogen-dependent mammary tumor cells (MCF-7 and MC4L2) and proliferation of triple-negative breast cancer (4T1) [162]. Pham et al. prepared six new nickel-Schiff base complexes with potential as lead complexes for DNA binding studies and also showed the ability to induce apoptosis in cancer cells [163]. Representative natural products coordinated with Ni²⁺ were displayed in Table 6.

Natural product-coordinated V^3+/4+/5+ self-assembly

Vanadium is one of the essential trace elements for the human body. As researched, it is extremely closely related to the human body's nervous, hematopoietic, cardiovascular systems and cholesterol metabolism, as well as the kidneys, liver and bones, affecting human health. Among the potential pharmacological effects of Vanadium compounds, its hypoglycemic and anticancer effects are the most noticeable. However, the toxicity of Vanadium should not be overlooked [163–165]. Several studies have been conducted to employ V-coordinated nanomedicines for in vivo tumor-selective therapy and imaging [166]. In a study, a simple one-step assembly method was utilized to successfully prepare a novel natural polyphenolic TA coordinated mixed-valence V oxide nanoparticles. V valence shift catalyzed the production of toxic ·OH from H₂O₂ to achieve tumor-specific CDT. In addition, NIR absorption enabled tumor PTT. In vitro and in vivo experiments showed that the synergistic strategy of CDT and PTT effectively inhibited tumor growth [167]. Hu et al. designed a V-based nanocomplex that coordinated vanadyl ions (VO²⁺) with TA and integrated filaggrin proteins (SS) through complex interactions. V-based nanocomplexes exerted a PTT effect that ablated in situ tumors and triggered ICD via endoplasmic reticulum stress to activate systemic immune responses for better suppression of distal tumors [168]. Zhang et al. proposed a mode of enhanced ferroptosis activation through modulation of tumor cell glucose metabolism by utilizing TA coordinated with V oxides and loaded with lonidamine (LND). Valence changes of V induced ferroptosis, while LND enhanced ferroptosis-induced immune activation by interfering with glucose metabolism. This synergistic treatment provides a new option for tumor therapy [80]. Representative natural products coordinated with V^3+/4+/5+ were displayed in Table 6.

Natural product-coordinated multiple metal self-assembly

Combined coordination of multiple metals is an effective synergy strategy for treating tumors. TA coordinated with Fe³⁺/Mn²⁺ loading with PD-L1 inhibiting DNAzyme to form an all-active component nanoplatform named MPNS. The valence transition of Fe³⁺ after entering tumor cells triggered ferroptosis, whereas DNAzyme activated by Mn²⁺ effectively silenced PD-L1. In the meantime, ferroptosis could activate the immune response by triggering ICD. Ferroptosis induced immunotherapy was applicable to the treatment of primary and distant tumors [169]. Additionally, amino acids were linked to DOX through click chemistry for the purpose of targeted drug release in the TME and MRI-mediated tumor therapy through the action of amino-coordination metal ions (Gd³⁺, Fe³⁺, and Mn²⁺) [170]. Singh et al. coordinated Zn²⁺ with CuO by sonochemistry and then modified the surface of the nanoparticles with folic acid-modified alginate coupled with polydopamine for targeted delivery of PTX for the treatment of breast cancer. It also further induced cell death by increasing intracellular ROS production for synergistic treatment of tumors with PTX chemotherapy and oxidative stress. To test the ability of NPs to generate ROS, the results detected with the DCFH-DA probe demonstrated that Zn²⁺ doping in the CuO skeleton significantly increased the PTX loading rate, and NPs-treated MCF-7 cells produced more ROS than free PTX [171].

Zeng et al. coordinated CoFe₂O₄ with gossypol and encapsulated it with glycerol monooleate (GMO) to form NPs. To verify the targeting properties of NPs, the investigators labeled NPs with IR780, which showed satisfactory tumor-targeting properties by in vivo fluorescence after injection into mice. In addition, they demonstrated by fluorescence imaging of isolated organs that the synthesized nanoparticles had better tumor site aggregation and longer tumor retention time compared to free IR780 [58]. Zhang et al. synthesized an ultra-small nanoparticle by the BCGN@L with Bi/Cu-GA coordination and then loaded polyvinylpyrrolidone and glucose oxidase (Gox). Upon arrival at the tumor site, GOx catalyzed glucose to produce gluconic acid and H₂O₂ for CDT. Glucose depletion reduced the expression of heat shock proteins (HSPs) and enhanced the sensitivity of PTT, resulting in a synergistic effect of CDT and PTT [123]. Liu et al. coordinated TA with Fe³⁺/Mn²⁺ and encapsulated it with Anti PD-L1 DNAzyme to form a fully active component nanoplatform. The valence state transition of Fe3 + entering tumor cells triggers ferroptosis, while Mn2 + activated DNAzyme effectively silences PD-L1. Meanwhile, ferroptosis can activate immune responses by triggering ICD, which is suitable for the treatment of primary and distant tumors (Fig. 8) [169]. Representative natural products coordinated with multiple ions were displayed in Table 6.

Fig. 8.

Schematic representation of a nanoplatform of TA coordinated with Fe³⁺/Mn²⁺ and encapsulated with Anti PD-L1 DNAzyme to form a fully active component and the combination of multiple therapeutics.

Copyright 2022, Wiley

Biological safety

Few studies have reported significant biotoxicity of metal ions when coordinated with natural products. Numerous studies have confirmed the good biodegradability and biocompatibility of the coordination with metal ions [102, 144, 156, 176]. Although a variety of metal-coordinated nanoparticles have been demonstrated to exert significant antitumor activity, there are still no clear standard to assess the biosafety of metal nanoparticles. Undoubtedly, the content of metal ions directly affects their toxicity. For example, iron overload causes biotoxicity, and the poor prognosis of many diseases is associated with it. In patients with severe iron loading, iron could cause severe organ damage and death [177]. Excessive intake of zinc ions could cause nausea, diarrhea and abdominal discomfort. In severe cases, it could adversely affect the lipid profile of the body and the immune system [178]. The daily intake of some trace elements copper, iron, manganese, molybdenum, selenium, and zinc is as follows: 0.3–0.5 mg, 1 mg, 55 μg, 19–25 μg, 60–100 μg, and 3–5 mg [179].

In addition, the toxicity of metal-coordinated nanoparticles depends on their biophysical properties such as size, specific surface area, surface charge and aggregation state [180]. Therefore, it is crucial to establish a standard for evaluating the safety of metal ions coordination.

Conclusion and perspective

The review summarizes the research advances in nanomedicines formed by natural products coordinated with metal ions for multimodal imaging and multi-modality combination therapy of tumors in the last 3–4 years. The metal ions listed are all essential metal elements in human body, these natural products are derived from various plant and animal extracts, natural ingredient derivatives, and microbial metabolites, which are combined with metal ions to create more unexpected effects from the original active ingredients. These nanomedicines are being extensively studied for treatment of tumors.

First of all, Sources of material for natural products are widespread. They are critical material to cure various diseases and mainly derived from various plants, animals, microorganisms and some natural product derivatives. Such as tannic acid, curcumin and other polyphenols extracted from a variety of plants. DOX extracted from the fermentation broth of Streptomyces bosaiensis var. sp. They have been widely investigated in nano-delivery field because their structural characteristics make them easy to coordinated assembly. These natural products possess various biological activities, and most of them are natural small molecules with high safety and unexpected development and utilization value.

Secondly, the coordinated self-assembled nanomedicine synthesis is green and simple. Natural products and metal ions are generally synthesized by simple ways such as stirring, ultrasonic, redox, and one-pot method due to the coordination effect as well as π-π stacking effect. The preparation processed simple, environmentally friendly and time-saving. Moreover, the particle size and other characteristics of nanoparticles can be controlled by adjusting the ratio of raw materials and the synthesis time, which is more convenient than the preparation of other new nanomaterials.

Thirdly, multiple imaging modalities and combined treatment of multiple modalities for tumors are hot topics in current research. Drug pathways as well as treatment effects are monitored through in vivo imaging. Obviously, combination therapy is promised to serve as an effective measure to ameliorate drug resistance in tumor cells. New functions emerged on the basis of the original efficacy due to the successful coordination of metal ions with natural products. The propensity of metal ions to coordinate with natural products is determined by a variety of chemical properties, including the charge density, electronic structure, and coordination geometry preference of the metal ion, as well as the electron-giving capacity and spatial configuration of the ligand in the natural product. Metal ions with higher electron cloud densities tend to coordinate with organic molecules containing more π-electrons or lone pairs of electrons, while metal ions with lower electron cloud densities tend to coordinate with molecules containing electronegative atoms such as oxygen and nitrogen. In natural products, functional groups (e.g., hydroxyl, amino, carbonyl, etc.) containing atoms such as oxygen and nitrogen are usually used as coordination sites. Metal ions such as Fe^2+/3+, Cu^+/2+, Zn²⁺, Ni²⁺ and other transition metal ions are often able to form stable coordination compounds with multiple coordination sites in natural products due to their variable oxidation states and strong field strengths. For example, Fe^2+/3+ and Cu^+/2+ are easy to change their valence states due to tumor environmental influences. Therefore, the nanomedicine coordinated with them exert CDT through amplify oxidative stress. The coordination of some metal ions (such as Mn²⁺/Cu²⁺/Fe^2+/3+) with natural products also shows photoacoustic signals, they are utilized to accurately measure and quantify vascular morphology, blood flow, monitor tumor oxygen/hypoxia status and the depth of drug reaching the tumor, etc. Even the diagnosis and surgery of complex diseases are guided by precise imaging. In addition, natural products can also be used in other therapeutic methods such as chemotherapy and immunotherapy due to their combination with metal ions, and have various imaging functions, such as enhanced magnetic resonance imaging of divalent manganese ions (Mn²⁺) and fluorescence imaging of rare earth metal ion complexes. In summary, if researchers want to develop nanomedicines for oxidative stress, they can preferably choose metal ions with easily changeable valence states such as Fe^2+/3+, Cu^+/2+, V^3+/4+/5+ to assemble with suitable natural products in coordination, which will endow them with excellent photo-thermal effects and amplified oxidative stress. If immune activation is required, Mn^2+/3+ and Zn²⁺ can be selected for coordination with suitable natural products to activate the body's own powerful immune response for primary as well as distant tumour treatment. In terms of imaging, Mn²⁺ is widely used in nuclear magnetic imaging. In addition, photoacoustic imaging can also be achieved through metal ions such as Fe^2+/3+, Cu^+/2+, Mn^2+/3+, etc.

In conclusion, this review lists a large number of studies describing the combination of multiple imaging modalities of PTI/FLI/PAI/MRI with CT/CDT/PTT/PDT/ICD/SDT for the treatment of tumors. It is proved that natural products coordinated with metal ions possess broad application prospects in treating tumors, fighting tumor drug resistance, and detecting and treating more complex tumors. However, there are still challenges in certain key technical routes and practical applications. The first is the safety issue, excessive metal ions will produce toxicity, so it is necessary to determine the ratio of raw materials and methods, and at the same time to keep the nanomedicine in the physiological state of stability, cannot be released prematurely to cause damage to the organism. Next is the stability problem, the formation of aggregated precipitates will make the particle size increase thus affecting the penetration rate. If the above problems can be solved, the nanomedicines have stable performance and can be released precisely. It is believed that the natural product-coordinated metal nanomedicines for multi-modality imaging-mediated multi-pathway tumor therapy strategy have a broad application prospect, and will be one of the indispensable pathways for future tumor therapy.

Author contributions

L.XY. and L.SY. collected resources and wrote the main manuscript text and design pictures; J.XY., L.HF. and W.XQ. participated in resource collecting of the article; S.KH., L.MF., W.P. and C.YX. participated in text proofreading of the article; W.TJ. and W.B. participated in the overall idea design and supervision of the article; Y.XA. designed, supervised, revised and edited the main manuscript. All authors reviewed the manuscript, all authors have approved the submitted version and have agreed both to be personally accountable for the author's own contributions.

Funding

National Natural Science Foundation of China (82104357); China Postdoctoral Science Foundation (2022T150441 and 2021M702292).

Availability of data and materials

No datasets were generated or analyzed during the current study.

Declarations

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All authors have read the journal policies and submit this manuscript in accordance with those policies. All authors agree to publish.

Competing interests

The authors declare that they have no competing interests.