Coordination chemistry-enabled drug delivery systems: metal-ligand platforms for controlled release and targeted therapeutics

Abstract

Coordination chemistry presents an ideal molecular platform for the development of superior drug-delivery systems that can be effectively released, selectively targeted, and integrated into functional therapeutic systems. Due to their predictable geometries and tunable bonding properties, metal ions can form a variety of structures, including coordination polymer nanoparticles (CPNs), metal-organic frameworks (MOFs), supramolecular coordination complexes (SCCs), and metal-ligand cross-linked hydrogels. These structures possess a high cargo-loading ability and are sensitive to physiologically significant stimuli, including pH gradients, redox imbalances, enzymatic activity, and light. In addition to drug encapsulation, metal centers are intrinsically imaging-contrastive, catalytic, magnetically responsive, and phototherapeutic, enabling synergistic, multimodal therapies. This review critically analyzes the principles of coordination underlying the rational design of these delivery platforms, the key classes of coordination-based carriers, and their applications in cancer therapy, antimicrobial and antiviral treatment, gene and protein delivery, and theranostics. Emerging trends, such as hybrid organic-inorganic-bimolecular systems, hierarchical self-assembly, and AI-directed design, have also been described as definite areas of transformation in next-generation therapeutics. Issues related to physiological stability, metal toxicity, immune response, and scalable manufacturing are discussed, along with means to support clinical translation. Coordination-based architectures are expected to give the next generation of precise therapeutics that facilitate spectacular regulation of molecular assembly, dynamic reactions, and treatment.

Graphical abstract

Highlights

Coordination chemistry enables programmable, stimuli-responsive drug delivery.

Metal-ligand platforms enable targeted, controlled, and multimodal therapeutics.

MOFs, CPNs, SCCs, and hydrogels have high loading and biological responsiveness.

Coordination systems combine imaging, therapy, and precision-medicine capabilities.

Hybrid architectures promote synergistic, adaptive, and clinically translatable delivery.

Introduction

Coordination chemistry in drug delivery: foundation and motivation

Coordination chemistry is a leading field for the next generation of drug delivery systems [1]. Metal ions exhibit predictable geometries, dynamic coordination behavior, and adjustable bond strengths with various ligands, making them a versatile molecular platform for a range of therapeutic applications. Unlike organic nanocarriers, metal-ligand assemblies are highly programmable. Their composition, spatial organization, and responsiveness are tightly regulated [2]. These features render delivery systems reliable for circulation, enable targeting of diseased tissues, and trigger drug release in response to physiological stimuli [3]. Metal-ligand coordination enables the folding of small molecules, nucleic acids, peptides, and proteins into stable metal-coordinated therapeutic platforms that exhibit enhanced release properties, improved circulation, targeted delivery, and enhanced anti-degradation. These systems, comprising metal-drug nanoparticles and metal-drug hydrogel systems, have a wide range of therapeutic applications in cancer, infectious diseases, gene therapy, and tissue repair (Fig. 1) [4].

Fig. 1.

Survey of metal-coordinated therapeutic systems. The binding of metal ions and the organization of various ligands, including small molecules, peptides, RNA, and DNA, form metal-drug nanoparticles and metal-drug hydrogels with enhanced pharmacokinetic and therapeutic effects, thereby enabling the controlled and sustained release, targeted delivery, pH responsiveness, extended circulation, enzyme protection, and synergistic metal-drug interactions. These systems have applications in cancer therapy, infectious disease treatment, gene silencing, mRNA cleavage, osteo-related diseases, uveitis treatment, wound healing, and antiviral or antibacterial therapy [4]. Reproduced under a CC BY-NC 4.0 license

As we learn more about the biological environment, coordination-based therapeutics have become increasingly popular. The effectiveness of drugs is not solely based on their molecular strength; it also depends on ensuring that the drug agents are delivered to the correct location, in the proper form, and at the right time, and these concepts are well supported by coordination chemistry [5]. The rational design of stimuli-responsive metal-ligand interactions, including pH-, redox-, enzyme-induced-, and photo-responsive interactions, is possible [6].

Traditional drug delivery systems, such as polymeric nanoparticles, liposomes, micelles, and dendrimers, have enhanced therapeutic efficacy but also have limitations [7]. Most of these approaches employ noncovalent interactions such as hydrophobic interactions or van der Waals forces [8]. This results in unstable variables, an inability to detect the environment, and a limitation in adding functionality such as imaging, catalysis, or multiple drug loads [9]. There are also many organic carriers with internal structures that cannot be loaded or released [10].

Coordination-based platforms utilize metal-ligand interactions to provide dynamic control and rigidity. These platforms address the limitations of the conventional systems. A coordination bond is an example of a molecular switch whose strength varies in response to ligand design, external stimuli, and environmental factors [11]. This results in structures that are resistant to physiological acidity, ionic strength, degradation in acidic tumors, reductive compartments, and enzymatic activity associated with infection and inflammation. Metal ions also exhibit optical, magnetic, and catalytic properties, enabling combined chemotherapy, phototherapy, hemodynamic therapy, and imaging [12].

Coordination chemistry describes the formation of coordination complexes between metals and ligands via Lewis base reactions, in which metal ions act as electron donors and ligands serve as donor atoms (i.e., N, O, or S). The coordination states and geometries of assemblies of coordinators are governed by essential parameters, including the metal’s oxidation state, coordination number, chelation strength, and kinetic lability; these parameters collectively determine carrier integrity and stimulus-induced dissociation. Mechanistic foundations of metal-ligand materials developed under these principles include coordination polymer nanoparticles, metal-ligand MOFs, supramolecular coordination complexes, and metal-ligand hydrogels. Specifically, rational ligand design can be used to implement selective coordination, as in the case of crown ethers, the macrocyclic cavities of which recognize metal ions to bind them by size- and fit-based affinity, which makes them predictable in their affinity and thus selective enough to be exploited to produce controlled assemblies and functional behavior.

A comprehensive overview of metal complexes and coordination chemistry in therapeutic applications was previously provided by Cohen et al. [13]. Building upon this foundation, the present review emphasizes key advances reported from 2021 to 2025, including emerging coordination-driven architectures, multi-stimulus logic-gated systems, AI-assisted design strategies, and improved translational considerations, such as biocompatibility, targeting, and scalable manufacturing.

Coordination-driven architectures for precision therapeutics

The most common platforms for controlled drug delivery, with increased accuracy, are coordination-based architectures. Small molecules, proteins, and nucleic acids can also be successfully trapped within structurally coherent and dynamic networks such as CPNs [14]. Due to their porosity, MOFs have superior loading capacity, tunable pore chemistry and controlled physical degradation. On the same note, SCCs offer nanocavities whose molecular control allows the specific entrapment and liberation of therapeutic agents [15]. Moreover, the mechanical strength and adaptive behavior of cross-linked metal-ligand hydrogels can be used to develop implantable or injectable depot systems that deliver drugs in a localized or sustained manner, for example, in topical applications [16].

The coalescence of these platforms demonstrates that several therapeutic functions can be coordinated into a single construct via coordination chemistry. The ligand design, the metal type, the topology, and the surface structures may be controlled systematically, enabling modular incorporation of features such as controlled release, targeting, imaging, and catalysis [17]. This enables drug carriers to achieve disease- or therapeutic-specific goals, underscoring the flexibility of coordination-based methods.

The current focus of precision medicine is personalized treatment techniques. Patient-specific biomarkers, tumor microenvironmental characteristics, and biological heterogeneity support these findings, and coordination-based systems organize these goals. Their structural and functional characteristics enable them to be selective to changes in biochemical variations between normal and diseased tissues. The site-selective activation of drugs and minimization of systemic toxicity were achieved using stimuli-responsive coordination bonds [18]. Molecular imaging with metals enables tracking of biodistribution and treatment.

Such coordinated systems can integrate multiple therapeutic pathways, thereby enabling the use of diverse treatment plans, which is essential for overcoming drug resistance, tumor heterogeneity, and disease progression. Metal platforms can be used to combine chemotherapy with photodynamic therapy (PTT), catalyze the generation of reactive oxygen species (ROS), facilitate immunomodulation, or deliver nucleic acids [19]. The outcome is a synergistic effect that is superior to that of single-modality treatment [20].

Scope and objectives of this review

This review discusses drug delivery systems based on coordination chemistry. The subsequent sections describe the effects of metal-ligand interactions on stability, response, and therapeutic performance. The primary structural types, including CPNs, MOFs, supramolecular complexes, and hydrogels, are also discussed. It outlines artificial procedures, chemical characteristics, and medical applications. Other therapies identified as exceptionally advantageous in the review include cancer therapies, antimicrobial and antiviral therapies, and gene and protein delivery, all of which utilize coordination systems. These systems are based on the combination of coordination chemistry with polymers, biomolecules, and inorganic nanostructures. This integration provides better responsiveness and a new functionality. This article is a critical review of research on translational problems and developments in the discipline. The latest developments include biomimetic coordination systems, multi-metal logic-gated structures, and scalable manufacturing.

Principles of coordination chemistry in drug delivery

Coordination geometries and structural determinants

Metal-ligand-based drug delivery systems exhibit coordination geometries. The steric effects, ligand-field stabilization energies, and electronic configurations of the metal ions determine their desired arrangement [21]. Common coordination networks include octahedral, tetrahedral, square planar, trigonal bi-pyramidal, and polymeric. These geometries control the spatial geometry of the ligands and the integrity of the obtained materials. They also influence the accessibility of cargo, porosity, and mechanical properties of supramolecular assemblies [22].

In extended networks, such as MOFs and metal-coordinated polymers, the geometry of the metal center is crucial to their functionality. Network topology, dimensionality, and pore structure depend on the geometry of the metal center [23]. Octahedral nodes are prone to forming robust three-dimensional structures that can maintain their shape even in physiological conditions [24]. On the other hand, tetrahedral or unsaturated coordinative centers are more flexible; in other words, ligand competition, variations in pH, or redox conditions can more readily disrupt these carriers [25]. To adjust the responsiveness and stability of coordination-based carriers, researchers need to tailor the geometric arrangement by selecting suitable metal and ligand combinations.

Electronic structure, ligand field strength, and binding dynamics

The systems of therapeutic coordination, based on metal-ligand bonding, are controlled by the laws of the ligand field theory, according to which d-orbitals of the metals are divided when they are bonded with the ligands. The geometry of the bonds, as well as the bond strength and kinetic lability, is primarily affected by ligand-field splitting. Kinetically inert strong-field ligands (i.e., phenanthrolines, bipyridines, phosphines and multidentate carboxylates) allow the formation of complexes, but have low ligand-exchange rates, which is a desirable characteristic when constructs are expected to survive in a systemic circulation. Pier weaker-field ligands (pyridines, imidazoles, simple carboxylates, thiolates, etc.) exhibit dynamic behavior that can be disassembled under physiological conditions [26].

Stability has also been found to be affected by ligand density through the chelate effect. Multidentate ligands are more thermodynamically stable and less dissociative, which makes them beneficial for applications that require long integrity [27]. Mono-dentate ligands, in their turn, are more permissive to the design of systems with adjustable release properties due to their ability to be easily replaced according to environmental stimuli [28]. The interplay among ligand-field strength, denticity, and electronic configuration provides the basis for rationally designed, stable, and flexible coordination systems [29].

Thermodynamic and kinetic stability in biological environments

The biological efficacy of drug delivery systems based on coordination is essentially dependent on achieving an optimal balance between thermodynamic and kinetic stabilities. The stability of the formation of metal-ligand complexes in thermodynamic terms is a measure of the general favorability of complex formation [30]. It can be used to predict the competitiveness of alternative ligands common in physiological fluids, including phosphates, bicarbonate, amino acids, and proteins. Although the formation constants are high, which makes the elements resistant to displacement, the thermodynamic stability is not a sufficient condition to ensure biological integrity [31].

The rate of ligand dissociation, which is the kinetic stability, is equally important. Slowly, ligand-exchange complexes are more likely to survive the dynamic physiology of the bloodstream without early cargo dissociation/release or metal ion leakage [32]. However, complexes that are too inert can be inaccessible for disassembly at the target site, thus restricting treatment activity [33]. As a result, a high degree of stability is achieved through meticulous modulation of ligand affinity, steric shielding of the metal center, design of the secondary coordination sphere, and the use of a microenvironment that excludes other biological ligands [34].

Stimuli-responsive modulation of coordination bonds

The inherent benefit of coordination-based drug delivery systems is their sensitivity to both physiological and external stimuli. The pH, redox potential, enzymatic activity, and light sensitivity of metal-ligand bonds enable molecular processes to permit or prohibit the release of cargo in a controlled or conditional manner [35].

The pH-responsive behaviour arises from the protonation of donor atoms in ligands, such as carboxylate, imidazole, catechol, and pyridyl groups [36]. Tumor endocytic compartments and tumor extracellular matrices have a lower pH than normal tissues, which disrupts coordination bonds and facilitates the breakdown of the frameworks [37]. Intracellular glutathione or other reductant gradients have also been exploited, and redox-responsive systems dissociate metal-ligand interactions with Fe³⁺, Cu²⁺, Co³⁺, and Ru-based centers upon reduction [38]. Photoresponsive coordination complexes are photodissociated, structurally rearranged, or reduced to be spatially activated by light irradiation [39]. Enzyme-responsive systems use peptide- or sugar-based ligands that are selectively cleaved by disease-associated enzymes, thereby altering the coordination environment and triggering controlled disassembly [40].

The ability of coordination bonds to act as molecular switches in response to both biochemical and physical stimuli is essential for the specificity of spatiotemporal control of therapeutic release [41]. Coordination-based drug-delivery platforms are designed to respond selectively to biochemical gradients and physical signals in diseased tissues. All these internal factors, such as pH, redox imbalances, or enzyme overexpression, and external factors, including light, heat, magnetic fields, and ultrasound, regulate the dissociation, rearrangement, or activation of metal-ligand bonds [42, 43]. The general topography of these endogenous and exogenous regulatory processes is shown in Fig. 2.

Fig. 2.

Schematic of external and internal stimuli controlling the coordination-based drug release. (a) Introduction of primary endogenous (pH, redox balance, enzyme activity) and exogenous (light, heat, ultrasound) triggers that can be applied to regulate metal-ligand interactions and drug release [42]. Biochemical stimuli (e.g., low pH, ROS, GSH, and MMPs) and external stimuli (e.g., light, magnetic field, heat, and ultrasound) can be combined to develop hierarchical, specific therapeutic stimulation in multi-stimuli-responsive coordination nanoplatforms [43]

Biocompatibility, clearance pathways, and design integration

To ensure an effective coordinated delivery system for biomedical use, the biocompatibility must be assessed in detail. It is essential to select metal ions because each metal has its own physiological properties, redox activity, and toxicity. Zinc, magnesium, calcium, and iron are biologically essential metals with good safety profiles, particularly when incorporated into structures that limit ion leakage. Although redox-active metals are beneficial in therapeutic approaches, they still require encapsulation to reduce off-target oxidative stress and prevent uncontrolled ROS generation [44].

Clearance pathways play an important role in the design of the material. Nanostructures smaller than the renal filtration threshold are likely to be quickly removed by the renal system, whereas assemblies larger than this size are excreted by the liver and spleen through uptake by the mononuclear phagocytic system [45]. The surface chemistry of these materials affects corona formation, opsonization, and immune recognition of proteins, thereby influencing their circulation time and biodistribution. Designers can also effectively tune the clearance and reduce unwanted interactions by tuning coordination stability, hydrophilicity, surface charge, and ligand composition [46].

Geometric control, electronic tuning, dynamic ligand exchange, and stimuli responsiveness are the bases for the development of sophisticated drug delivery systems [47]. Coordination chemistry can be used to design carriers that behave predictably across a range of biological environments while retaining the flexibility required to act specifically upon activation [48]. These principles are the mechanistic concepts for building the main classes of coordination-driven nanocarriers, as discussed further in this review, and for the rational design of platforms that can address the more complex needs of precision medicine.

Metal-based nanocarriers and coordination-driven architectures

Overview of coordination-driven nanostructures

Coordination chemistry provides nanocarriers with a structural and mechanistic foundation for their design, controlled composition, topology, and functional behavior [49]. Nodes that can bond to two or more ligands are termed metal ions and can lead to the formation of multiple architectures at the nanoscale, depending on their size, pore size, and dynamics. Such architectures include CPNs, metal- and organic-framework coordination structures, SCCs, and metal- and ligand-cross-linked hydrogels [50]. The association of these classes with one another is facilitated by the various assembly modes, which are linked by the need for interaction between metals and ligands, thereby providing them with stability, responsiveness, and modularity. The selective presence of metal centers, ligand structures, and assembly conditions permits the production of systems that can survive during circulation and react selectively with acidic, reductive, enzymatic, or photo-induced signaling [51]. Together, these coordination resources provide a versatile set of drug-delivery systems, enabling personalized therapeutic action across a wide range of disease applications [52]. Figure 3 summarizes the synthesis of coordination structures, their drug-loading behavior, and their downstream therapeutic use, illustrating how coordination chemistry integrates material production, cargo loading, and translation across several therapeutic situations [53]. In addition, Table 1 presents a comparative summary of the significant coordination-based nanocarriers, their structural determinants, stimuli-responsive characteristics, and their therapeutic applications.

Fig. 3.

Schematic diagram of coordination, synthesis, loading, and therapeutic delivery of metal-ligand systems. The figure highlights MOF synthesis from metal centers and organic ligands, drug loading into porous cage structures, characterization of the drug-loaded framework, and representative therapeutic/biopharmaceutical applications, including antimicrobial/antiviral treatment, pulmonary delivery, wound healing, and ocular therapy [53]

Table 1.

Summary of coordination-driven nanocarriers: structural characteristics, stimuli responses, and therapeutic applications

Nanocarrier type	Metal ions commonly used	Representative ligands	Structural features	Stimuli-responsiveness	Cargo types	Advantages	Limitations	Typical therapeutic uses	Notes	References
CPNs	Fe³⁺, Zn²⁺, Mg²⁺, Zr⁴⁺	Catechol, polyphenol, carboxylate, imidazole	Amorphous or semi-crystalline networks	pH, redox	Small molecules, peptides, proteins, nucleic acids	Mild aqueous synthesis, high loading, biocompatibility	Dilution stability, competitive ligand exchange	Cancer therapy, protein delivery, antimicrobial	Highly modular via ligand denticity	[54, 55]
MOFs	Zn²⁺, Zr⁴⁺, Fe³⁺, Cu²⁺	Imidazolate, dicarboxylate, porphyrin ligands	Crystalline porous lattices	pH, redox, and enzymatic	Hydrophobic drugs, hydrophilic drugs, biomacromolecules	Ultra-high porosity, tunable pores	Phosphate sensitivity, serum instability	Combination therapy, PDT, imaging	Ideal for co-delivery	[56]
SCCs	Pt²⁺, Pd²⁺, Ru²⁺, Fe²⁺	Polypyridyl, bipyridine, phenanthroline	Discrete cages, helicates, polyhedra	pH, light, ligand-exchange	Small hydrophobic drugs, imaging agents	Molecular precision, predictable host–guest effects	Complex synthesis, dilution instability	PDT, DNA-targeting	Tunable cavity size	[57]
Metal-Ligand Hydrogels	Fe³⁺, Ca²⁺, Zn²⁺, Mg²⁺	Catechol, histidine, carboxylate	3D polymeric networks	pH, redox, and enzymatic	Proteins, growth factors, small molecules	Injectable, self-healing, tissue-like mechanics	Limited systemic use	Local therapy, wound healing	Excellent depot systems	[16, 58]
Polyphenol-Based CPNs	Fe³⁺, Mn²⁺	Tannic acid, gallic acid	Dynamic supramolecular shells	Acidic pH	DOX, CPT	High stability at pH 7.4	Rapid degradation in a strong acid	Cancer therapy	Good for endosomal release	[59]
Porphyrin-MOFs	Zr⁴⁺, Fe³⁺	Porphyrin linkers	Light-absorbing frameworks	Light, pH	Photosensitizers	High PDT efficiency	Limited deep-tissue penetration	PDT	Strong ROS generation	[60]
Magnetic Coordination Nanoparticles	Fe³⁺, Fe²⁺	Polyphenols, catechols	Magnetically responsive cores	Magnetic field, pH	DOX, siRNA	External targeting	Possible aggregation	MRI-guided therapy	Enables magnetic hyperthermal	[61]
Gold-Coordination Hybrids	Au³⁺/Au⁰	Thiols, phosphines	Nanoshell or cluster hybrids	Light	Hydrophobic drugs	High photothermal conversion	Potential toxicity	Photothermal therapy (PTT)	Useful for multimodal therapy	[62]
Lanthanide-MOFs	Gd³⁺, Eu³⁺, Tb³⁺	Multidentate chelates	Luminescent or MRI-active frameworks	Enzymatic, pH	Imaging probes, drugs	Theranostic imaging + delivery	Metal leakage concerns	Imaging-guided therapy	Long emission lifetimes	[10]
Redox-Active CPNs	Cu²⁺, Fe³⁺	Polyphenol	Redox-cycling networks	Reductive GSH	CDT agents, drugs	Synergistic ROS + drug release	Off-target ROS possible	Chemodynamic therapy	Enhanced in the tumor microenvironment	[63]

Coordination polymer nanoparticles

CPNs are dynamic, structurally integrated assemblies produced by the coordination of multidentate metal ions and organic ligands into networks on the nanometer scale. The inherent versatility of metal-ligand bonds enables CPNs to integrate structural coherence and environmental responses [64]. The standard classes of ligands include polyphenols, catechols, polydentate carboxylates, and imidazole-rich molecules, which are often complexed with iron, zinc, magnesium, or zirconium [65]. These varieties generate networks that can entrap a broad range of therapeutic agents, including peptides, small molecules, proteins, and nucleic acids [66].

Mild aqueous synthetic accessibility facilitates high loading efficiency, macromolecular bioactivity, and scalable fabrication. The degradation behavior of the latter is very well controlled by modulating the denticity of the ligand, stability of metal-ligand interactions, or secondary coordination interactions [54]. For example, polyphenol-based CPNs are highly sensitive to acidic pH, dissolve under tumor or endosomal conditions, and are stable at physiological pH [67]. Circulation, biodistribution, and cellular uptake can be further improved by surface modification via the covalent or coordination-based grafting of targeting moieties, PEGylation (PEG) chains, or charged ligands [68]. These characteristics make CPNs flexible systems suitable for systemic and localized drug delivery.

CPNs are generally prepared by rapid complexation of metal ions with ligands, followed by growth to form coordination networks at the nanoscale. The crosslink density and coordination kinetics are regulated by the metal-to-ligand ratio, ligand dentate, solvent polarity, and competing biomolecules, and ultimately determine particle size and stability. CPNs have several benefits, including high drug-loading capacity, modular composition, and strong stimuli-responsive behavior, but also have several weaknesses, including batch-to-batch variability, premature dissociation in complex biological fluids, and limited long-term structural homogeneity.

MOFs as porous delivery vehicles

MOFs are among the most structurally advanced coordination-driven drug carriers [69]. The structures were synthesized using clusters of metal ions linked by rigid, multidentate organic ligands, resulting in crystalline structures with incredibly high internal surface areas and pore dimensions that can be reshaped. The porous structure of MOFs enables the facile loading of hydrophobic drugs, hydrophilic compounds, imaging agents, and biomacromolecules via processes ranging from diffusion-driven adsorption to direct coordination to the metal nodes [70].

Examples of prototypical MOFs used in biomedical studies include zinc imidazolate frameworks, zirconium UiO-O frameworks, iron carboxylate frameworks, and MIL-like structures [71]. Zinc-based structures, including ZIF-8, exhibit strong pH sensitivity; they remain stable at physiological pH but decompose rapidly under mildly acidic conditions, enabling on-target intracellular delivery [72]. Zirconium MOFs are highly stable and biocompatible (owing to the strong O bond of zirconium), allowing them to regulate and release drugs in a sustained manner over prolonged periods [73, 74]. MOFs based on iron possess inherent magnetic and redox-active functionalities that can be used to image or treat diseases via chemotherapies [75].

Strategies used to evade immune clearance, tumor accumulation, and controlled pharmacokinetics include surface engineering, such as polymer coating, lipid bilayers, peptide-targeting ligands, folate-targeting ligands, and camouflaging into biomimetic membranes, which allows MOFs to be targeted to the tumor [76]. Their ability to co-encapsulate multiple agents in different pore environments has been utilized to develop combination therapy platforms for the co-delivery of chemotherapeutics, photosensitizers, immunomodulators, or nucleic acids [77].

MOFs can be formed by solvothermal or room-temperature assembly of metal nodes and multidentate organic linkers into crystalline porous structures. Drug loading can occur during synthesis via entrapment within pores, and drug release can occur via post-synthetic diffusion into the framework, or it can be affected by MOF stability under physiological stimuli such as acidic pH or redox conditions. MOFs offer significant benefits, including high porosity and loading capacity, tunable pore chemistry, and predictable architecture; however, their biomedical applications are limited by stability issues in aqueous or ionic solutions and potential metal leaching. Large-scale reproducible production can be difficult.

Supramolecular coordination complexes

SCCs are isolated, self-assembled nanoscale structures defined by their size and shape, and are governed by the geometric complementarity between metal centres and coordinating ligands [78]. SCCs are discrete, self-assembled metal-ligand architectures (e.g., polygons and polyhedra). In this review, the term “coordination cages” is used specifically to describe 3D cage-type SCCs capable of guest encapsulation. They are virtually constructed around square-planar metal ions, such as platinum and palladium, or octahedral metal ions, such as ruthenium and iron, to form well-defined structures, such as metallocages, helicates, polyhedra, and molecular barrels [79]. Tiny cavities ideally adapted to entrap hydrophobic drugs, small nucleic acids, or imaging molecules are produced by these assemblies [80].

The SCCs of the molecules are molecularly accurate, allowing for predictable host-guest interactions and permitting the size of the cavity, surface charge, and binding affinity to be systematically changed through systematic ligand modification [81]. Their metalloligand contacts are dynamic enough to be stimulus-responsive; cage opening or selective release may be affected by simple changes in ligand exchange and pH, or by reducing, oxidizing, or exposing the cage to light [82]. Other photophysical properties are available for ruthenium-cage systems; therefore, PDT and molecular encapsulation can be combined [83].

The key issues associated with SCCs are that they are sensitive to the dilution of biological media and synthetically complicated to produce ligands with the correct geometry and rigidity. Nevertheless, ligand design, aqueous self-assembly, and surface modification are yet to be enhanced to advance their use in biomedical applications.

The thermodynamically controlled coordination of metals by ligands creates discrete cages, polygons, or well-defined architectures of SCCs, whose ultimate geometry is determined by directional bonding preferences and ligand architecture. Complementary and noncovalent host-guest interactions, including size- and shape-based interactions, tend to entrap therapeutic guest molecules, allowing their retention and release on demand. The benefits of SCCs are that they have a specific molecular structure, definite stoichiometry, and can control the guest encapsulation, but they are often characterized by the fact that they have a low payload capacity as compared to porous materials, are sensitive to dilution or ligand exchange in biological media, and their synthesis is more complex than that of porous materials.

Metal-ligand cross-linked hydrogels

Metal-ligand-cross-linked hydrogels are three-dimensional polymer networks in which coordination interactions act as dynamic crosslinking points [84]. The pendant groups on the polymer backbones, including catechol, histidine, carboxylate, and phosphonate, react with metals such as iron, zinc, calcium, and magnesium to form hydrogels with tailored mechanical and degradation behaviors [85]. These hydrogels combine the high water content and tissue-like softness of polymeric gels with the reversibility of coordination-chemistry bonding [86].

The self-healing and shear-thinning properties of the metal-ligand crosslinks are attributed to their dynamic nature, which enables them to be readily injected and in situ gelled [87]. The mechanism of drug release involves passive diffusion, coordination dissociation, or network degradation, which is based on pH, redox, or enzymatic stimuli [88, 89]. Their biocompatibility and mechanical flexibility make them suitable for localized therapy, wound healing, tissue regeneration, and the post-surgical delivery of chemotherapeutics or protein therapeutics [90].

Metal–ligand hydrogels form via coordination cross-linking between polymer-bound ligands (e.g., catechol, histidine, or carboxylates) and metal ions, yielding a three-dimensional network stabilized by reversible, dynamic coordination bonds. Their mechanical strength and drug-release kinetics depend on crosslink density, metal identity, and ligand-exchange rates, which collectively govern network stability and responsiveness in physiological environments. These hydrogels provide key advantages, including injectability for localized delivery, self-healing behavior, and sustained depot-style release; however, their performance may be constrained by slower diffusion-controlled release, potential swelling or instability under certain conditions, and limited suitability for systemic circulation-based delivery.

Comparative summary of coordination-driven carrier classes

Each category of coordination-based carrier is integrated to provide a distinctive balance across the structural level, environmental versatility, cargo-carrying capacity, and translation application. Key features of polymer nanoparticles as coordination polymers include ease of synthesis, biodegradability, and functionalization [70]. Metal-organic frameworks are characterized by high porosity and multicomponent loading capacity; however, the skeleton must remain stable in phosphate-rich biological solutions, necessitating careful design [71]. The advantages of SCCs include the accuracy of their molecular structures and their photophysical tunability [72]. However, there are challenges associated with large-scale preparation and dilution. Metal-ligand hydrogels are optimal for the local delivery of drugs to different areas, but not in the bloodstream [1].

A comparative overview of the formation mechanisms, advantages, limitations, and preferred therapeutic scenarios of these coordination-driven carrier classes is summarized in Table 2. It is essential to understand these differences to choose an appropriate platform. Metal identity, coordination topology interplay, and ligand structure are factors that not only influence physicochemical characteristics but also affect therapeutic index, biological fate, and suitability for a given disease. Additional routes elaborate on this architectural category, discussing metal-specific behavior, therapeutic mechanisms, and the sphere of application in greater detail.

Table 2.

Comparison of coordination-driven carrier classes: formation mechanism, advantages, limitations, and preferred applications

Platform	Typical formation mechanism	Key advantages	Key limitations	Preferred applications / best-use scenarios	Reference
Coordination polymer nanoparticles (CPNs)	Rapid metal–ligand complexation in solution followed by nucleation and growth into nanoscale coordination networks; size and stability governed by metal/ligand ratio, ligand denticity, solvent conditions, and competing biomolecules.	High drug loading; modular composition; strong responsiveness to endogenous stimuli (pH/redox); feasible surface functionalization.	Batch-to-batch variability; possible premature dissociation in biofluids; less structural uniformity than crystalline systems.	Systemic nanomedicine delivery; stimuli-responsive chemotherapy; multifunctional nanoplatforms (therapy + imaging).	[54, 91]
Metal–organic frameworks (MOFs)	Self-assembly of metal nodes and multidentate organic linkers into crystalline porous frameworks via solvothermal or mild synthesis; drug loading via pore encapsulation or post-synthetic diffusion; release governed by framework stability/degradation.	Very high porosity and loading capacity; tunable pore chemistry and degradation; controllable architecture and multifunctionality.	Stability challenges in aqueous/ionic environments; potential metal leakage; complex scale-up and reproducibility.	High-capacity loading of small molecules/biomolecules; pH-responsive tumor delivery; theranostics and catalytic therapy platforms.	[92, 93]
SCCs	Thermodynamically driven self-assembly into discrete cages/polygons through directional metal–ligand coordination; guest loading by size/shape complementarity and host–guest interactions.	Precise molecular definition; predictable stoichiometry; selective encapsulation and controlled release; excellent structure–function control.	Lower payload than porous carriers; sensitivity to dilution/ligand exchange; synthetic complexity and cost.	Targeted delivery of potent drugs; controlled host–guest release; molecular theranostics and precision-triggered activation.	[5–95]
Metal–ligand hydrogels	Formation of 3D polymer networks through reversible coordination crosslinking (e.g., catechol/imidazole/carboxylate ligands with metal ions); mechanical properties depend on crosslink density and ligand exchange kinetics.	Injectable/local delivery; sustained depot release; self-healing and shear-thinning behavior; high biocompatibility potential.	Diffusion-limited release; swelling/instability risk; less suited for systemic circulation; mechanical tuning required.	Localized therapy (wound healing, tissue repair, post-surgical sites); long-acting drug depots; regenerative medicine scaffolds.	[96, 97]

Metal ions in therapeutic coordination systems

Overview of metal selection principles

Selection of metal ions is a key parameter in the design of coordination-based drug delivery systems. Metals exhibit distinct redox and physicochemical properties, as well as coordination preferences and biological interactions. All these factors determine the responsiveness and stability of the drug carrier, as well as their biocompatibility, therapeutic functions, and imaging potential [69]. Therefore, it is crucial to comprehensively understand metal-specific coordination chemistry to develop predictable platforms that are tunable for drug release and demonstrate reduced toxicity. Table 3 presents an overview of the most essential metal ions in therapeutic coordination systems, along with a comparative analysis that highlights their chemical properties, reactivity to stimuli, biocompatibility, and functionality as drug-delivery carriers.

Table 3.

Metal Ions in Therapeutic Coordination Systems: Chemical Properties, Biological Roles, and Delivery Functions

Metal ion	Oxidation states	Coordination geometry	Key chemical feature	Biological compatibility	Stimuli responsiveness	Therapeutic role	Typical delivery platform	Advantages	Concerns	References
Fe³⁺/Fe²⁺	+ 3/+2	Octahedral	Strong catechol affinity	Essential metal	Redox-sensitive	CDT, drug delivery	CPNs, MOFs, hydrogels	Biocompatible, catalytic	ROS overproduction	[98]
Cu²⁺/Cu⁺	+ 2/+1	Square planar, tetrahedral	Strong redox cycling	Moderately biocompatible	Reductive GSH triggers	CDT, prodrug activation	CPNs, MOFs	Strong catalytic ROS	Cytotoxicity	[99]
Zn²⁺	+ 2	Tetrahedral	Non-redox metal	High biocompatibility	pH-sensitive	Acidic tumor release	ZIF-8, MOFs	Safe, predictable	Rapid acidic degradation	[100]
Zr⁴⁺	+ 4	Octahedral/12-coordination	Very strong metal–O bonds	Highly biocompatible	Enzymatic/pH	Sustained release	UiO-MOFs	Exceptional stability	Slow degradation	[101]
Pt²⁺/Pt⁴⁺	+ 2/+4	Square planar/octahedral	DNA binding	Cytotoxic	Reduction-activated	Chemotherapy prodrugs	Pt-complex MOFs	Strong anticancer effect	Nephrotoxicity	[102]
Ru²⁺	+ 2	Octahedral	Photodissociation	Good tolerability	Light-triggered	PDT, photo-prodrugs	SCCs	Precise activation	Requires light access	[103]
Au³⁺/Au⁰	+ 3/0	Linear, trigonal	Strong thiol affinity	Moderate	NIR photothermal	PTT	Gold hybrids	Highly efficient PTT	Accumulation risk	[104, 105]
Gd³⁺	+ 3	8–9 coordinate	High relaxivity	MRI-approved	None (stable)	Imaging-guided therapy	Lanthanide-MOFs	Strong MRI contrast	Chelation essential	[106]
Tb³⁺/Eu³⁺	+ 3	8–9 coordinate	Narrow emission bands	Biocompatible when chelated	Luminescent	Optical imaging	Lanthanide cages	Time-gated imaging	Free ion toxicity	[107]
Co³⁺/Co²⁺	+ 3/+2	Octahedral	Hypoxia-triggered	Limited	Reductive	Hypoxia-activated delivery	Co-complexes	Tumor-specific activation	Toxicity at high doses	[108]

The following sections present the key groups of metals, noble metals, transition metals, and lanthanides, and elucidate how their coordination properties affect their performance in therapeutic uses.

Transition metals in coordination-driven drug delivery

Coordination-based delivery systems are based on transition metals, which are well-suited to the system due to their variable oxidation states, redox reactivity, and varied coordination geometries [109]. Due to its compatibility with the human body and its natural abundance in biomass, iron has been extensively utilized. Ferric ion (Fe³⁺) easily forms strong coordination interactions with polyphenol, catechol, carboxylate, and hydroxamate ligands to produce stable MOFs, CPNs, and hydrogels. The Fe³⁺/Fe²⁺ redox ratio provides active reactivity that can be applied to in pH-controlled degradation or redox-mediated therapeutic approaches, including chemodynamic therapy (CDT) [110].

Copper is another vital transition metal used in therapeutic coordination complexes [63]. The Cu²⁺/Cu⁺ redox couple confers sensitivity to intracellular reducing conditions, especially in cancer cells with enhanced glutathione levels [111]. The copper complexes may be reduced by controlled dissociation, enabling release of the encapsulated cargo or activation of prodrugs. Moreover, copper-based coordination polymers and MOFs are not only catalytically active and can produce ROS, but also exhibit synergistic or independent anticancer effects [112].

Zinc, which is not involved in any physiologically relevant redox cycling process, exhibits excellent biocompatibility and a pH-responsive profile [72]. Zincimidazole structures, such as ZIF-8, have been extensively used in nanomedicine because of their ZnN coordination bonds, which are stable at neutral pH but dissociate at a relatively weak acidic pH. This property enables the selective release of drugs into the tumor and endosomal compartments [113].

Although cobalt and nickel are uncommon due to their association with toxicity concerns, they exhibit beneficial coordination properties in certain situations [114]. Cobalt complexes can also use a Co³⁺/Co²⁺ redox pair to support ligand exchange under hypoxic or reducing conditions [115]. On the other hand, nickel is mainly used in affinity-based systems, where Ni2+-histidine reactions are used to conjugate proteins or deliver them to engineered receptors [116].

Calcium and magnesium as biocompatible coordination nodes

Alongside transition-metal nodes typically employed in coordination therapeutics, main-group metal ions such as calcium (Ca²⁺) and magnesium (Mg²⁺) are highly biocompatible and physiologically important coordination elements that should be considered in the design of drug-delivery systems. These ions are selective for oxygen-donor ligands (e.g., carboxylates, phosphates, and catechols), enabling them to form reversible cross-linked networks and bioactive assemblies at relatively lower toxicity costs than most redox-active metals. Ca²⁺ and Mg²⁺-based coordination interactions are also useful in injectable hydrogels, tissue engineering scaffolds, and systems that mimic mineralization, in which ionic crosslinking can provide mechanical reinforcement and controlled release, with good biodegradation and clearance properties. Nevertheless, due to the generally lower coordination numbers and reduced redox abilities of Ca²⁺ and Mg²⁺ ions, their assemblies may require optimisation with ligands or fusion to other motifs to achieve adequate stability at physiological ionic strengths.

Noble metals and their photophysical and catalytic functions

Most transition metals lack the structural and functional complexity of noble metals such as Ru, Pt, Pd, and Au. Their strong ligand fields, inertness, and extensive photophysical capabilities make them vital for the development of SCCs and phototherapeutic systems [117].

Ruthenium plays a vital role in therapeutic coordination chemistry [118]. The primary characteristics of octahedral Ru²⁺ polypyridyl complexes are their strong coordination stability, variable electronic absorption in the visible spectrum, and ability to photodissociate upon exposure to light. These properties enable the creation of photoactivatable prodrugs and supramolecular cages that release their cargo only upon light irradiation, providing spatial resolution superior to that of traditional delivery systems [119]. Moreover, ruthenium complexes are intrinsically cytotoxic via various mechanisms, including DNA binding or the photoreactive generation of ROS, and thus cannot be limited to drug-delivery applications [120].

Platinum remains a part of cancer therapy, primarily because of its proven effectiveness in cisplatin-based chemotherapy [121]. Pt(IV) complexes are used in the drug delivery field, in which the octahedral structure of the complex is stable in the systemic circulation of the drug, and the reduction of cells to Pt(II) restores the square-planar geometry necessary for interaction with DNA [105]. Tumor selectivity, reduced systemic toxicity, and co-delivery of synergistic therapeutic agents are enhanced by modifying Pt(IV) complexes in MOFs or coordination polymer networks [122]. Although uncommon, Pd exhibits distinct catalytic properties. Nanostructures containing palladium or supramolecular complexes have the potential to be used as sites for bioorthogonal reactions in vivo, wherein prodrugs can be activated by the creation of carbon-carbon or carbon-heteroatom bonds within tissues. This catalytic action enhances the range of the targeted activation of prodrugs [123].

The affinity of gold for sulfur-based ligands and its ability to undergo efficient photothermal conversion make gold-based coordination hybrids invaluable for PTT [124]. Gold nanostructures complexed with thiolated ligands exhibit enhanced stability and fine-tunable surface chemistry, making them suitable for converting near-infrared (N-IR) light into limited heat to induce tumor ablation [125, 126].

Lanthanides in theranostics and imaging-guided delivery

Lanthanide ions are essential for coordination-based therapies owing to their unique magnetic, luminescent, and radiological properties [127]. The trivalent lanthanides, gadolinium, europium, terbium, and dysprosium, have electronic configurations that contribute to their long-lived emissions, paramagnetism, and high X-ray attenuation. These characteristics enable lanthanide coordination systems to serve as theranostic agents for imaging and drug-delivery applications [128].

Gadolinium (Gd) is extensively used as an MRI contrast agent. Upon insertion of Gd³⁺ into MOFs or coordination complexes, it provides high relaxivity and the ability to co-encapsulate therapeutic agents. This combination of imaging and therapeutic functionality allows real-time tracking of drug distribution and release characteristics [129]. Typical luminescence, narrow emission bands, and long lifetimes characterize complexes of Eu and Tb, which have enabled the use of time-gated imaging to maximize signal-to-noise ratios in biological applications [130]. The magnetic anisotropy of dysprosium is sufficiently large to support hyperthermia treatment, and the same element has a smaller magnetic anisotropy. Therefore, it can be used as a contrast agent in imaging applications [131].

The design of a coordination platform incorporating lanthanides requires careful attention to ligand stability, as premature release of free lanthanides can lead to toxicity. These problems can be addressed using multidentate chelators and MOF-based environments, which are firmly bound and enable safe and effective in vivo use.

High-valency metals and toxicity constraints

Actinide ions, such as thorium and uranium, have also been of interest as conceptual building blocks in high-valency coordination structures, owing to their large ionic radii and high coordination numbers. Their ability to form stable complexes with high charge densities provides an opportunity to develop polynuclear assemblies with topological features [111]. However, radiotoxicity, environmental effects, and regulatory constraints significantly limit their use in therapeutic settings [112]. As a result, actinides are still largely academic, only trying to understand the behavior of coordination, as opposed to their use in practical drug delivery systems.

The introduction of metals into therapeutic platforms requires a thorough analysis of their toxicity, biodistribution, and continuing biocompatibility. The biomedical use of highly toxic metals (mercury, cadmium, and lead) is prohibited due to their undesirable health hazards [113, 114]. Even metals considered safe may cause adverse effects if discharged into coordination structures or remain in tissues for extended periods [115]. Redox-active metals can form ROS, and dense inorganic nanoparticles composed of noble metals or lanthanides can accumulate in the liver or spleen without biodegradation [116].

Plans for toxicity reduction include the use of metals tested for toxicity, high-affinity chelators that inhibit metal leakage, incorporation of metal centres into a protective coordination shell, and degradation of excretable fragments [117]. A thorough understanding of metal pharmacokinetics, clearance pathways, and biomolecule interactions is fundamental to the successful clinical application of coordination-based therapeutics [118].

Integrating metal-specific properties into therapeutic design

The diversity of coordination behavior across different metals enables the creation of nanocarriers tailored to specific therapeutic requirements. Redox-active transition metals are dynamically responsive and catalytic; noble metals have photophysical and therapeutic properties; lanthanides are used for delivery in a manner that can be imaged; and biocompatible metals are safe and biodegradable [132, 133]. By leveraging the distinctive characteristics of a given metal in coordinated architecture, scientists can create sophisticated delivery systems that integrate, accumulate at a designated site, utilize multimodal therapy, and can be monitored in real time. Thus, the positioning and composition of metal ions are practical tools for developing better therapeutic platforms.

Coordination chemistry strategies for controlled drug release

Overview

Controlled drug release is a crucial goal of modern therapeutic systems, and coordination chemistry offers a distinctly versatile molecular structure for achieving this objective. The reversibility and sensitivity of metal-ligand interactions to environmental factors enable fine control over the timing and location of drug release from their vehicles [25]. Physiologically significant stimuli, such as pH gradients, variations in redox potential, enzymatic activity, and light exposure, tune coordination bonds in predictable ways, thus permitting the selective activation of diseased tissues and reducing systemic toxicity [134]. The coordination environment, metal-ion identity, ligand structure, and framework topology all play important roles in the mechanism and kinetics of drug release [135]. Researchers can create delivery systems that provide spatiotemporal resolution of action by designing coordination systems that respond to endogenous cues in the microenvironment or to exogenous clinical stimuli. A schematic overview of endogenous stimuli within the tumor microenvironment, such as pH gradients, redox imbalance, enzyme overexpression, hypoxia, and ROS elevation, which regulate the behavior and activation of nanoscale carriers [136], is shown in Fig. 4. Overall, Fig. 4 highlights that endogenous tumor-associated gradients (pH, redox imbalance, enzyme overexpression, and ROS elevation) provide coordinated biochemical “switches” that enable selective destabilization of carriers in diseased tissues. This trend supports the increasing design focus on multi-trigger responsiveness to improve spatiotemporal control while minimizing off-target release under normal physiological conditions. The key stimuli-responsive mechanisms used in coordination-based drug delivery systems are summarized in Table 4, where each is accompanied by its corresponding chemical principle, responsive metal-ligand motif, representative material, and therapeutic impact. As summarized in Table 3, a key trend is that coordination platforms achieve controlled release by tuning bond lability and framework stability in response to specific stimuli, with pH/redox triggers being the most widely exploited for intracellular activation. The table also indicates that multi-stimuli strategies are increasingly adopted to improve selectivity, although they introduce higher design complexity.

Fig. 4.

Schematic representation of endogenous stimuli-responsive liposomes and tumor-associated biochemical triggers. Liposomal nanocarriers responsive to intrinsic tumor-related cues, including pH, redox potential, enzyme activity, hypoxia, and ROS levels. These endogenous gradients mediate structural destabilization and drug release, thereby enabling targeted antitumor activity. Hydrophobic and hydrophilic therapeutic agents are encapsulated within the bilayer, and selective activation in tumor tissues leads to cancer cell death [136]

Table 4.

Stimuli-responsive coordination release mechanisms: principles, materials, and applications

Release trigger	Mechanistic basis	Responsive metals	Sensitive ligands	Representative materials	Typical cargo	Advantages	Limitations	Disease applications	Trigger specific notes	References
pH	Protonation weakens bonds	Zn²⁺, Fe³⁺, Mg²⁺	Imidazole, catechol, carboxylate	ZIF-8, Fe-polyphenol CPNs	DOX, CPT	Tumor selectivity	Off-target in acidic organs	Oncology, infection	Strongest between pH 5–6	[137]
Redox	Reduction alters the metal state	Fe³⁺/Fe²⁺, Cu²⁺/Cu⁺, Co³⁺/Co²⁺	Polyphenol, N-donors	Fe-CPNs, Cu-MOFs	Prodrugs, ROS agents	Tumor-selective	Risk of excess ROS	Cancer (CDT)	GSH-triggered	[73]
Light	Photocleavage or isomerization	Ru²⁺, Pt⁴⁺, Au³⁺	Polypyridyl, azobenzene	Ru-SCCs, Pt-prodrugs	Photosensitizers	Precise activation	Requires irradiation	PDT, PTT	Deep-tissue NIR possible	[138]
Enzyme	Cleavage of peptide linkers	Zn²⁺, Ca²⁺, Fe³⁺	Peptide, glycosidic	Enzyme-MOFs, hydrogels	Peptides, antibiotics	High specificity	Patient variability	Cancer, inflammation	MMP-sensitive	[139]
Hypoxia	Metal reduction in low O₂	Co³⁺	N-donor ligands	Co-complexes	Prodrugs	Tumor specificity	Limited oxygen gradient depth	Solid tumors	Works best in necrotic cores	[140]
Multi-stimuli	Combined pH+redox+light	Fe³⁺+Ru²⁺ etc.	Hybrid ligands	Hybrid MOFs	Multi-drug	High precision	Design complexity	Oncology	Sequential activation	[141]
ROS	H₂O₂ reacts with metal	Fe²⁺, Cu⁺	Polyphenol	CDT-MOFs	ROS-generating drugs	Synergy with CDT	Non-selective ROS	Cancer	Often paired with a pH response	[22]
Enzyme + pH	Sequential cleavage	Zn²⁺, Ca²⁺	Peptide + carboxylate	Hybrid hydrogels	Proteins, cytokines	Biological precision	Slow degradation	Regenerative	Ideal for local therapy	[141]
Magnetic	Thermal activation	Fe₃O₄	Polyphenol shells	Magnetic CPNs	Drugs, siRNA	External control	Heating limits	Hyperthermia	MRI-visible	[142]
Thermal	Heat-driven dissociation	Au°, Fe²⁺	Soft donor ligands	PTT hybrids	Hydrophobic drugs	Spatial control	Heat-affected tissues	Tumors	NIR-based PTT	[143]

Stimuli-responsive mechanisms (pH/redox/light/enzyme)

pH-responsive release via proton-mediated modulation of coordination bonds

pH-responsive coordination systems use differences in acidity between physiological compartments. Mild acidity is characteristic of the extracellular environment of tumors; however, intracellular organelles, such as endosomes and lysosomes, exhibit even lower pH values [144]. These gradients serve as intrinsic stimuli for the protonation of the donor atoms in the ligands, thereby dilating the metal-ligand interactions and releasing the ligands in a controllable manner.

When used as MOFs, imidazolate ligands become protonated, rapidly destabilising the Zn-N bond and leading to structural degradation and the release of cargo encapsulated within ZIF-8. Correspondingly, the pH-stimulated dissociation of iron polyphenol CPNs relies on the protonation of catechol groups, enabling either gradual or burst release of drugs, depending on the extent of protonation and the mechanical limitations of the network. pH-responsive metal poly-hydrogels are CPNs whose dissociation is determined by the presence of catechol groups, which are protonated to release or burst-release drugs gradually [145].

The ability to tune the pH sensitivity through ligand substitution, denticity, electron-withdrawing or donating functional groups, and secondary coordination effects enables the fine-tuning of the release profile [146]. Stable windows of coordinate-system design based on physiological fluctuations in pH enable targeted interventions in acidic disease microenvironments.

Redox-responsive mechanisms and reduction-induced ligand dissociation

Redox-responsive coordination systems capitalize on the substantial redox potential differences between extracellular and intracellular environments. Increased reductants, including glutathione, are often observed in tumor cells and serve as a precursor to redox-induced coordination changes [147]. Changes in oxidation state can occur in metals (e.g., Cu, Fe, and Co), thereby altering ligand affinity and coordination geometry [148]. Iron-based systems can be considered canonical models [118]. Weakening coordination to polyphenol or carboxylate ligands by reducing Fe3 + to Fe2 + results in faster dissociation and subsequent cargo release [149]. Similarly, copper complexes can be reduced from Cu²⁺ to Cu⁺ to form redox-active species capable of releasing drugs and catalyzing the generation of ROS, thereby increasing CDT and cytotoxic effects. The Co³⁺ to Co²⁺ transition is used by cobalt complexes to regulate ligand-exchange rates, enabling selective activation in hypoxic or reductive tumor environments [150]. A representative collaborative strategy is CDT combined with chemotherapy, in which Fe- or Cu-based coordination systems generate intracellular ROS while simultaneously releasing chemotherapeutics (e.g., doxorubicin). At the cellular level, elevated ROS disrupt mitochondrial membrane potential, increase lipid peroxidation, and enhance DNA damage, thereby sensitizing tumor cells and promoting apoptosis or ferroptosis.

The overall redox responsiveness of these systems can be precisely tuned through thoughtful ligand design. Depending on judicious ligand choice to stabilise a particular oxidation state or on the incorporation of redox-active cofactors that alter the electron-transfer pathway, redox-responsive behaviour can be engineered [151]. This method enables the formation of carriers that are selectively activated by a specific redox potential within the cell, particularly in the presence of high concentrations of reducing agents.

Light-activated release via photocleavage and photoisomerization

Extrinsic regulation of drug delivery is non-invasive and is controlled by light-responsive coordination systems that deliver drugs with high spatial and temporal resolution [152]. Photoactive metal complexes (particularly Ru, Pt, and Ir) undergo a process in which the ligand dissociates, the structure rearranges, or is photoreduced upon exposure to irradiation. These processes lead to the rupture of coordination bonds, the freezing of coordinated drugs, or the disintegration of supramolecular structures, thereby releasing encapsulated molecules [153].

Ruthenium polypyridyl complexes have potential for photoactivation. Ru-L bonds photodissociate upon exposure to visible light to release ligands and/or cause disintegration of cages in supramolecular assemblies [154]. The photoreduction of platinum(IV) complexes may restore their ability to bind DNA, leading to cytotoxicity in light-illuminated tissues [155]. Photoisomerizable organic ligands (e.g., azobenzenes in coordination networks) can also undergo trans-cis isomerization, thereby disrupting steric interactions and destabilizing the ligand skeleton [156].

Modulation of release profiles may also be based on the wavelength, intensity, and duration of light exposure [157]. The improvement of systems sensitive to N-IR light, which can penetrate deeper into tissues, enhances the potential of photoresponsive coordination platforms [158].

Ultrasound (acoustic)-triggered release

Ultrasound is also a clinically significant external stimulus for drug delivery because it provides deep tissue penetration, is noninvasive, and can deliver energy to a specific area. However, compared with optical activation, which is limited by tissue scattering and absorption, ultrasound enables activation of deeper lesions with spatiotemporal control. The properties of ultrasound make it a suitable complement to light-responsive coordination systems in environments requiring deep-tissue activation.

Thermal and mechanical effects, including localized heating, cavitation, and microstreaming, can be induced by ultrasound in coordination-based carriers, thereby accelerating diffusion, disrupting carrier integrity, or destabilizing metal-ligand crosslinks reversibly. The release can thus be triggered by ultrasound in a coordination hydrogel, a hybrid nanocarrier, or a polymer-metal network that has mechanically labile or thermally responsive coordination motifs. These strategies facilitate on-demand release and may minimize systemic exposure, thereby enabling localized therapy with improved dosing and activation control.

Magnetic-field-triggered release

Another non-invasive strategy that offers external control is magnetic-field-responsive drug delivery, which is particularly appealing for deep tissues where optical penetration is suboptimal. The activation of magnets is usually attained by the integration of magnetic materials, in the majority of cases, iron oxide nanoparticles, into coordination networks, coordination polymer networks, or metal-ligand hydrogels. In addition to triggering release, magnetic guidance can improve site-specific accumulation prior to activation, thereby enhancing localization and minimizing off-target exposure.

Localized hyperthermia or magneto-mechanical stimulation of magnetic materials can be induced by alternating magnetic fields and can enhance drug diffusion and partially disrupt coordination cross-links, thereby inducing controlled release. Multimodal therapeutic approaches also include incorporating magnetic-responsive coordination systems, i.e., integrating controlled drug delivery with magnetic hyperthermia or imaging guidance. Overall, magnetic-field-triggered coordination carriers provide a flexible platform for externally regulated therapy, with the potential for greater precision in deep-seated disease settings.

Enzyme-triggered release through ligand cleavage and framework remodeling

Enzyme-responsive coordination systems employ ligands that serve as substrates for enzymes implicated in a specific disease. Specific ligand functionalities may be selectively cleaved or altered by various enzymes found in tumor, inflammatory, or infected tissues, including proteases, phosphatases, glycosidases, and oxidoreductases [159]. Enzymatic cleavage alters the coordination environment by either eliminating donor groups or destabilizing structural motifs, thereby inducing the controlled degradation of the carrier [160].

Metal-organic frameworks with peptide linkers (which are substrates of matrix metalloproteinases) are selectively degraded in tumors with high protease content [161]. Phosphorylated ligand-based coordination polymers are cleaved by alkaline phosphatases, thereby enabling coordinated degradation and drug release [162]. Enzyme-sensitive hydrogels contain peptide or saccharide motifs that alter the crosslink density in response to enzyme activity, thereby facilitating drug diffusion [163].

The selectivity of enzymatic reactions enables localization of pathology within a microenvironment with high molecular specificity. Enzyme-cleavable ligands combined with metal nodes, which control the kinetics of dissociation, add an extra degree of control by which release can be regulated [163].

Multi-stimuli and engineering design

Multi-stimuli-responsive systems integrating coordination triggers

Redox conditions, pH, enzyme activity, and oxygen levels co-occur in many biological tissues [164]. The response of mixtures of multi-stimuli-responsive coordination systems combines ligand architectures or metal centres that are responsive to multiple types of cues, enabling hierarchical or conditional control of release processes [165]. For example, pH-sensitive, redox-sensitive ligand-stabilized structures can be maintained at physiological pH and low reductant concentrations; however, they are degraded only exceptionally in acidic and reductive tumor environments [166]. Photoactive metal nodes on MOFs bearing proton-responsive ligands can also exhibit dual-stimulated behavior, enabling localized activation and improved spatiotemporal control. Such logic-gated behavior supports collaborative treatment by restricting intracellular drug release to tumor-associated compartments, thereby increasing effective drug concentration and reducing off-target exposure. At the cellular level, sequential activation can enhance therapeutic outcomes by improving uptake and endosomal escape, amplifying ROS-mediated stress, and promoting apoptosis or ferroptosis.

Multiresponsive hydrogels may include pH- or redox-sensitive coordination crosslinks, as well as preloaded inorganic nanoparticles sensitive to a magnetic field or near-infrared light [167]. These sophisticated regimes encourage multistep delivery plans, including tumor buildup, mid-level structural modifications in response to the microenvironment, and eventual activation of drugs by light [168].

Engineering release profiles through coordination design

Many parameters, such as ligand affinity, steric protection, ligand density, pore structure, and tertiary coordination interactions, can be regulated on a small scale to control the release kinetics of coordination-based carriers [26]. The high binding affinity of ligands delays drug release and enhances their stability in the systemic environment [169]. The monodentate properties or low binding affinity of ligands promote rapid or stimulus-responsive release. The pore structure and framework morphology play an essential role in determining diffusion pathways and encapsulation efficiency. The availability of competing ligands in biological fluids is controlled by the addition of hydrophobic pockets or secondary spheres surrounding metal centers [170].

The exceptional merit of coordination chemistry lies in its ability to control release behaviour through molecular design. With careful adjustment of these parameters, drug carriers can be designed to achieve narrow temporal resolution, which can be beneficial for acute therapy with rapidly delivered drugs and for chronic treatment with drugs with longer half-lives [171].

Targeted drug delivery using coordination systems

Overview of targeting strategies in coordination-driven platforms

Targeted drug delivery enhances therapeutic efficacy by localizing the active agents to specific disease tissues, while minimizing off-target exposure [172]. Coordination-based nanocarriers are particularly suitable for targeted delivery due to the structural flexibility of metal-ligand interactions, which enables the control of surface chemistry and the combination of various biological recognition entities [173]. These systems can be used to generate selective cell interactions, receptor-mediated uptake, or site-specific activation by combining strategic ligand incorporation with targeting motifs or by leveraging the natural metal-affinity patterns of biological tissue [3]. The targeting paradigms are illustrated in Fig. 5 [174]. Therefore, coordination chemistry not only provides a structural framework for drug transportation but also forms a mechanistic basis for biological discrimination [175].

Fig. 5.

Coordination mechanisms of active and passive targeting of drug delivery systems. Active targeting is based on receptor-specific ligands (antibodies, peptides, aptamers, organelle-targeting motifs, and small molecules). In contrast, passive targeting exploits the physicochemical accumulation effect (enhanced permeability and retention). Various nanocarriers, including liposomes, polymers, magnetic nanomaterials, metal oxide particles, and mesoporous silica, have been utilized to achieve selective delivery and enhance therapeutic precision [174]

In addition to ligand-based active targeting, numerous coordination-based nanosystems rely on passive targeting, particularly in solid tumours, where leaky vasculature and compromised lymphatic drainage can promote preferential accumulation of nanoparticles via the enhanced permeability and retention (EPR) effect. The efficiency of passive targeting is highly dependent on the particle size and shape, surface charge, and hydrophilicity, all of which affect the circulation time, extravasation, and biodistribution. To enhance systemic circulation and prolong the duration of surface engineering (e.g., PEGylation or zwitterionic coatings), strategies that reduce opsonization and increase the likelihood of surface accumulation at disease sites can be employed. Nevertheless, passive targeting can be highly heterogeneous across tumor types and patients and can be constrained by biological factors, including dense extracellular matrices and fluctuating perfusion, underscoring the importance of combining passive targeting with other targeting or activation platforms.

Ligand-based targeting through surface functionalization

Ligand-mediated targeting is a promising technique for directing carriers to specific tissues or cell types through their coordination with specific ligands [176]. CPNs, MOFs, supramolecular cages, or coordination hydrogels can be conjugated with functional ligands, such as folic acid, RGD peptides, antibodies, antibody fragments, aptamers, and small-molecule receptor-binding agents [177].

Folate-functionalized carriers exploit the overexpression of the folate receptor in several epithelial cancers [178]. MOFs can be covered with folate-bearing polymers or covalently bound to folate residues, thereby increasing tumor accumulation/internalization [179]. Similarly, RGD peptides bind to tumor vasculature-bound integrin receptors, enabling the delivery of therapeutic cargo to angiogenic endothelial cells and tumor-invading fronts [180].

Functionalization of antibodies and aptamers increases specificity for tumor-associated antigens [181]. Such ligands are loosely bound to a coordination site via metal-ligand anchoring, covalent interactions via peripheral functional groups, or secondary interactions [182]. These carriers exhibit increased tumor penetration, reduced systemic toxicity, and high uptake by malignant cells.

Metal-coordinative targeting based on biological affinity

Along with ligand-mediated reactions, specific metal ions exhibit a natural affinity for biomolecular structures, which allows direct targeting strategies based on coordination chemistry [183]. The affinity of substances can be redirected to bind or interact with biomolecules, such as histidine-rich proteins, nucleic acids, and phosphate-containing species, through metal-binding domains [184, 185]. The nickel-histidine coordination motif has widespread applications in protein purification and biotechnology, and analogous reactions can be used to agglomerate engineered receptors or histidine-tagged therapeutic proteins. Ni²⁺ or Co²⁺ coordination site carriers can interact with histidine-tagged cell surface markers or recombinant constructs for target internalization [186].

Cell membrane areas or areas in the backbone of nucleic acids rich in phosphate may serve as natural sites for cationic metal complexes [187]. SCCs or metal-containing nanoparticles can be tailored to bind negatively charged phospholipid surfaces or DNA structures [188]. They can be directed to a specific population of cells or the intracellular environment. These are two opposing views of receptor-ligand recognition based on metal coordination, from which the targeting properties of coordination-based systems can be extrapolated.

Magnetic targeting using iron-containing coordination nanoparticles

Magnetic targeting is an externally regulated technique that directs drug-loaded nanocarriers to specific tissues using magnetic fields [189]. Iron-based coordination nanoparticles, MOFs, coordination polymers, and hybrid composites containing iron oxide are magnetically responsive, enabling navigation with external magnets [190].

Systemically administered magnetic carriers can be targeted to tumor sites or inflamed tissues by utilizing local magnetic gradients. When accumulated, alternating magnetic fields can induce localized hyperthermia via Néel or Brownian relaxation [191]. Hyperthermia not only promotes tumor cell destruction but also increases vascular permeability and drug penetration. Combined with pH- or redox-sensitive coordination chemistry, magnetic targeting can enable multistage therapeutic activation, that is, preliminary magnetic concentration followed by subsequent release under a stimulus [192].

The magnetic performance, biodegradability, and biocompatibility of iron-containing coordination environments can be optimized by tuning key parameters of magnetic targeting systems, including particle composition, surface chemistry, and magnetic responsiveness [193]. In addition, imaging modalities such as MRI further enhance the functionality of these platforms by enabling real-time tracking of biodistribution and target-site accumulation [194]. While magnetic targeting remains a well-established external strategy, other energy fields can also support improved localization of nanosystems. Ultrasound, for example, can enhance vascular permeability and transiently permeabilize cell membranes (sonoporation), thereby promoting deeper tissue penetration and increased uptake of nanocarriers. Moreover, ultrasound-induced microstreaming and acoustic radiation forces may facilitate intratumoral transport, supporting localized delivery in deep anatomical regions where optical approaches are less effective.

Light-based strategies, although constrained by limited penetration depth, can also enable spatially confined targeting via photothermal guidance or photoactivated retention, particularly at superficial tumors or endoscopically accessible sites. Collectively, externally applied energy fields provide complementary routes to improve local drug concentration and spatial precision of coordination-based therapeutic carriers, either alone or in combination with passive accumulation and ligand-mediated targeting mechanisms.

Nuclear-targeting strategies enabled by metal complexes

Specificity to the cell nucleus is especially relevant for therapies based on DNA-damaging agents, gene-editing technologies, and transcriptional pathway modulators. Metal complexes, particularly platinum and ruthenium, exhibit an intrinsic affinity for DNA through covalent binding or intercalation. These interactions can be exploited using cationic surface-engineered SCCs and complexes, or planar aromatic ligands, to achieve nuclear accumulation [195, 196].

Moreover, t he nuclear localization sequences may be conjugated with coordination carriers for active transport by the nuclear pore complex. Supramolecular coordination structures with high charge density or ligand geometry have been shown to translocate into the nucleus with greater efficiency than most organic nanoparticles [197]. The intracellular pharmacodynamics of carriers may be tightly controlled by carrier designs that release their cargo upon nuclear entry, for example, via redox-mediated ligand exchange or photoactivation [198].

A significant problem is achieving a balance between the effectiveness of nuclear delivery and controlled activation to avoid damaging uninfected cells. Coordination chemistry provides the tunability necessary to maximize these competing factors to make atomic delivery operational only under the appropriate conditions [199].

Multi-modal targeting through integrated coordination design

Complex diseases often require multifactorial approaches that combine biochemical recognition with physical or microenvironmental stimuli. These comprehensive approaches require coordination-based systems because they enable the addition of multiple features within a single structure [200]. An MOF can be equipped with folate ligands for receptor-mediated uptake, iron nodes to direct it to cells via a magnet, and pH-sensitive ligands to release it selectively into cells [201]. Targeted peptides can be incorporated into CPNs together with redox-responsive metal centers to enable uptake by receptor-rich tissues and activation in reductive intracellular environments [202].

The term collaborative treatment is used in this review to describe synergistic treatment outcomes achieved through the coordinated application of drugs and an alternative modality, such as chemodynamic therapy (CDT), phototherapy (PDT/PTT), or immunomodulation. Cellular: Cellular synergy is often mediated by increased intracellular uptake, stimulus-induced release under acidic or reductive conditions, ROS-induced mitochondrial dysfunction, amplification of DNA damage, promotion of apoptosis/ferroptosis, and remodeling of the microenvironment to enhance drug sensitivity. This coordination chemistry is structured in a modular form, and this aids the integrated design paradigm. The surface functionalities, encapsulated cargo, ligand scaffolds, and metallic nodes can be programmed to respond specifically to a particular biological signal, thereby enabling synergistic targeting [193]. These multimodal assemblies enhance accretion of the target site, cellular uptake and regulated multistage delivery of therapeutics [194, 201].

Design considerations for optimizing targeting performance

Several design parameters need to be taken into consideration to deliver the optimum targeted delivery, and these are the size of the particles, the surface charge, the density of the ligand, the stability of the metal and ligand, and the degradation behaviour. An excess of ligands may result in steric hindrance or immune-mediated rejection, whereas a shortage of ligands may reduce binding specificity [203]. The stability needs to be fine-tuned so that the targeting ligands do not dissociate in the blood but can be disintegrated in the target tissue [178]. Additionally, targeting efficacy is influenced by the type of metal used, biodistribution, and potential interactions between the metal and biomolecules. Within the context of coordination chemistry and the biological constraints that underlie targeting efficacy, coordination-driven systems are founded. This is because high-quality design balances selective binding, desired activation, desired pharmacokinetics, and low off-target interactions [204].

Coordination chemistry in cancer therapeutics

Overview of coordination-driven approaches to cancer treatment

Drug delivery systems based on coordination are an influential and sophisticated area of application in cancer therapy [205]. Tumor biology is a complex area that encompasses heterogeneous environments, multidrug resistance (MDR), immune evasion, and abnormal vasculature, and requires delivery platforms capable of implementing specific spatial and temporal resolutions to provide therapeutic delivery [206]. To address these problems, coordination chemistry offers versatile molecules. Metal-ligand scaffolds could entrap, coordinate or conjugate therapeutic molecules; selectively respond to acidic or reductive tumor microenvironments; generate therapeutic ROS; or offer photothermal and photodynamic uses [207]. Those peculiarities allow the coordination-based systems to enhance drug accumulation, minimize systemic toxicity, and, at the same time, regulate several cancer-related pathways. Table 5 summarizes a review of the primary coordination-based therapeutic modalities in oncology, their mechanisms, their contributions by metal, their benefits, and their usefulness in the clinic.

Table 5.

Coordination chemistry in cancer therapeutics: mechanisms, platforms, and clinical advantages

Therapeutic modality	Mechanism enabled by coordination chemistry	Representative metals	Example platforms	Key advantages	Limitations	Tumor microenvironment interactions	Drug types delivered	Clinical relevance	Notes	References
Chemotherapeutic Delivery	Encapsulation in MOFs/CPNs	Fe³⁺, Zr⁴⁺, Zn²⁺	ZIF-8, UiO-66, Fe-CPNs	Stability, controlled release	Competitive ligand exchange	Acidic release	DOX, PTX	Widely applicable	Improves solubility	[51]
Metal-Based Prodrugs	Reductive activation	Pt⁴⁺→Pt²⁺, Ru²⁺	Pt(IV) complexes, Ru cages	Low systemic toxicity	Requires activation	Reductive tumor cytosol	Pt drugs	Cisplatin alternatives	Light-activatable	[208]
PDT	ROS from excited metals	Ru²⁺, Zr⁴⁺	Porphyrin-MOFs, Ru-SCCs	High singlet oxygen	Limited penetration	Hypoxia-dependent	Photosensitizers	Deep tumor therapy	NIR improves depth	[209]
PTT	Heat generation	Au°, Pd²⁺	Au-hybrids, Pd-nanostructures	Local ablation	Thermal collateral effects	Increased perfusion	Hydrophobic drugs	Minimally invasive	Strong synergy with chemotherapy	[210]
Chemodynamic Therapy	Fenton/Fenton-like	Fe²⁺, Cu⁺	Fe-MOFs, Cu-CPNs	Intracellular ROS	Off-target ROS	High H₂O₂ tumors	ROS agents	Drug-resistant tumors	Strengthened by acidic pH	[211]
MDR Reversal	Carrier-shielded drugs	Fe³⁺, Ru²⁺	CPNs, SCCs	Efflux circumvention	Tumor heterogeneity	Elevated GSH improves activation	DOX, CPT	Addresses resistance	Can co-deliver inhibitors	[212]
Theranostics	Imaging + therapy	Gd³⁺, Fe³⁺, Ru²⁺	Gd-MOFs, Fe-CPNs	Real-time tracking	Complexity	MRI-visible accumulation	Drugs + imaging	Precision oncology	Multimode signals	[75]
Targeted Delivery	Ligand or metal-affinity targeting	Fe³⁺, Zn²⁺	Folate-MOFs, RGD-CPNs	High specificity	Ligand shedding	Receptor-rich tumors	Most drugs	Improves biodistribution	Key for precision medicine	[51]
Redox-Activated Therapy	GSH-triggered release	Cu²⁺, Fe³⁺	Redox-MOFs	Tumor-selective	High GSH variability	Reductive cytosol	Prodrugs	Intracellular targeting	Synergizes with PDT	[98]
Multi-Modal Platforms	Combined PDT/PTT/CDT	Fe³⁺+Ru²⁺+Au°	Hybrid MOFs	Synergy	Formulation complexity	Multipathway activation	Multi-agent	Advanced oncology	Next-gen systems	[213]

Delivery of conventional chemotherapeutics through coordination frameworks

Traditional chemotherapeutic compounds such as doxorubicin, paclitaxel, gemcitabine, and camptothecin greatly benefit from encapsulation with coordination-based carriers [214]. The challenges frequently faced by these drugs include their low aqueous solubility, dose-limiting toxicity, clearance, and nonspecific biodistribution [215]. SCCs, MOFs, and CPNs provide structurally known microenvironments that can overcome these limitations effectively [216, 217].

The example of doxorubicin shows that this drug has a high affinity for the coordination network because it is aromatic and contains metal-binding functional groups. Their integration into MOFs allows them to be stable in circulation and released in response to pH in an acidic tumor microenvironment [179, 216]. Doxorubicin can be successfully encapsulated in a coordination polymer nanoparticle based on iron-polyphenol or zinc-carboxylate by coordination motifs that can be broken down once the particle enters the cell due to acidification [218]. In contrast, coordination cages (3D SCCs) provide ideal encapsulation at the molecular scale, with internal hydrophobic cavities optimally sized to accommodate aromatic small-molecule chemotherapeutics [105, 219].

The encapsulation of these carriers reduces the rapid release of drugs, enhances tumor uptake owing to passive and active targeting, and allows the incorporation of stimuli-responsive release [220]. Moreover, localized degradation mechanisms prevent burst release and provide long-term drug exposure at the tumor site.

Metal-based prodrugs and activation through coordination dissociation

Metal-containing prodrugs are intense pharmacotherapy regimens in which the pharmacological potential of the metal complex is not expressed until its activation in the tumor microenvironment [221]. An example of this approach is the use of Pt (IV) prodrugs, which are stable in the blood because they are in an octahedral form and are thus not activated prematurely [222]. When intracellular reductants are taken up by cells, they reduce Pt (IV) to Pt (II) to release axial ligands and restore the DNA-binding ability. This mechanism is further enhanced by the incorporation of a Pt (IV) prodrug in coordination carriers to increase the circulation time, tumor accumulation, and combination therapy [223].

Ruthenium complexes constitute the major group of prodrug metals. Such Ru-based complexes may undergo ligand exchange, aquation, or redox-activated activation, leading to the generation of cytotoxic species that attack DNA or produce ROS [224]. It is important to note that a variety of ruthenium complexes exhibit lower systemic toxicity than their platinum counterparts and can be activated by light through their photophysical properties [120]. Photoresponsive metal complexes have been used to achieve accurate spatial resolution of therapeutic activation [225]. Specifically, gold coordination systems may be thiol-reactive and responsive to visible light, allowing selective intracellular activation in glutathione-rich environments and facilitating interactions between the nucleus and the nucleoli (Fig. 6).

Fig. 6.

Schematic representation of the targeted cancer therapy using light-activated gold coordination complexes. (A) Reaction of GSH with thiol-reactive complexes of Au(III) under visible light. (B) The photocaged system of coumaplatin, which releases nuclear DNA upon light exposure, resulting in apoptosis, senescence, and antigen-immune activation [225]

Enhancing photodynamic and photothermal therapies through coordination chemistry

PDT and PTT are minimally invasive therapies that are used to induce local tumor ablation [226]. Nanocarriers based on coordination supplement these two modalities by improving the stability of photosensitizers, enhancing their photophysical characteristics, and enabling the co-delivery of chemotherapeutic agents [19].

An example of such synergetic interactions is the porous porphyrin-based MOFs. The porous character of the structures allows the incorporation of photosensitizers in highly spatially confined configurations, thereby enabling efficient energy transfer and singlet oxygen production upon irradiation [227]. Ruthenium complexes, particularly polypyridyl complexes, are dual-function agents that combine photosensitizing abilities with coordination-based encapsulation or controlled release functions [228].

Gold nanostructures coordinated with thiolated ligands, palladium nanomaterials, and iron oxide hybrids are used in PTT to convert light or magnetic energy into local heat [229]. Examples of coordination-based photoresponsive cancer therapies, including MOF-based nanotherapeutics that respond to UV, visible, NIR, and X-ray light to integrate imaging and treatment, are shown in Fig. 7 [230]. The combination of these materials into coordination frameworks improves the heat distribution, targeting, and multimodal therapeutic methods. An intricate coordination-based therapeutic effect of PDT or PTT in combination with chemotherapy is an increase in tumor penetration, drug resistance, and overall cytotoxicity [231].

Fig. 7.

Anticancer therapeutic modalities based on coordinated photoresponsive MOF. MOF-based nanotherapeutics can be activated by a variety of wavelengths (UV, visible, NIR, and X-ray) and enable imaging of nanotherapeutics (MRI, CT, PET, OI, and PAI) and therapeutic mechanisms (PTT, PDT, CDT, and radiation-driven therapy). The engineered MOF structure boosts localized activation, tumor accumulation, and multimodal therapeutic responses [230, 232]

CDT therapy and ROS generation through metal catalysis

CDT utilizes metal reactions in the tumor microenvironment to generate cytotoxic ROS. Tumors are often known to contain high levels of hydrogen peroxide, and metals such as iron and copper have the potential to undergo Fenton or Fenton-like reactions, where H₂O₂ is transformed into highly reactive hydroxyl radicals [233].

MOFs or CPNs based on iron provide a large number of Fe³⁺/Fe²⁺ redox sites, which generate ROS upon exposure to hydrogen peroxide. ROS generation leads to oxidative stress, mitochondrial damage, lipid peroxidation, and apoptosis. Cu²⁺/Cu² cycling has been used to achieve similar results in copper-based systems [234, 235]. Moreover, conventional chemotherapy, phototherapy, and immunotherapy can be combined with CDT to increase the therapeutic efficacy against multipathway cytotoxicity [236].

Catalytic activity is accurately controlled through coordination platforms by varying ligand identity, metal accessibility, and microenvironmental responsiveness. This rule reduces off-target toxicity and maximizes ROS production in tumors [237].

Overcoming multidrug resistance through coordination-driven strategies

MDR is a significant issue in chemotherapy and is mainly caused by augmented efflux pump activity, reduced intracellular drug concentrations, improved DNA repair, and altered signaling pathways [237]. Various approaches have been proposed to overcome these resistance mechanisms by using coordination-based carriers. The physical protection of drugs through encapsulation in MOFs or coordination polymers prevents efflux pumps from releasing drugs directly into the cytosol or the nucleus [238]. Metal complexes, especially ruthenium and gold complexes, enter cells via routes distinct from those used by standard organic drugs; thus, they are less susceptible to efflux. Moreover, efflux pump inhibitors can be co-delivered with chemotherapeutic agents via their coordination carriers, thereby disrupting resistance pathways [239].

Moreover, redox homeostasis is impaired by ROS produced by metal action, rendering resistant cells more susceptible to apoptosis. The carriers are redox-responsive and degrade preferentially under conditions of higher glutathione levels, which is one of the hallmarks of resistant tumors, and therefore guarantees the delivery of carriers to the locations with the highest resistance [240]. All of these mechanisms position coordination-based systems as powerful agents to restore the sensitivity of chemotherapeutic agents.

Integration of imaging and therapy through theranostic coordination platforms

Coordination chemistry is used in the context of therapeutic and diagnostic applications to combine diagnostic and therapeutic capabilities on a single platform, enabling real-time tracking of drug delivery, release dynamics, and therapeutic effects. MOFs with lanthanides or iron exhibit magnetic resonance imaging (MRI) contrast, whereas ruthenium, europium, and terbium complexes exhibit optical imaging [241]. Gold and platinum systems can be used in computed tomography imaging, whereas copper-based systems can be used for positron emission tomography or photoacoustic imaging [242].

The theranostic potential can be specifically helpful in oncology because the possibility of tracking tumor response and regulating treatment plans in real time maximizes effectiveness and reduces adverse effects [243]. The integration of multimodal imaging and multipathway therapy into a monolithic metal-ligand system is an essential benefit of coordination-based cancer therapy [244].

Summary and outlook for coordination chemistry in oncology

The innate structural accuracy, stimulus detection, and polyfunctionality of coordination chemistry have led to enormous breakthroughs in cancer therapy [244]. The use of coordination-driven systems, including classical drug delivery, metal-based prodrugs, phototherapy, CDT, and MDR reversal, is effective in overcoming the many limitations of traditional chemotherapeutics. Their ability to combine targeting ligands, imaging agents, and a variety of therapeutic modalities into a unified system meets the requirements of modern precision oncology [245].

Continued improvements in ligand design, hybrid structures, and AI-driven optimization will boost the possibilities of coordination-based cancer therapies [246]. Advancements in these technologies promise to provide safer, more effective, and individualized anticancer treatments.

Coordination chemistry in antimicrobial and antiviral delivery

Overview of metal-ligand strategies in infectious disease treatment

The increasing incidence of antimicrobial resistance, chronic viral infections, and new pathogenic agents has necessitated the development of delivery systems that can overcome biological barriers, penetrate protective biofilms, and maintain therapeutic drug concentrations at the foci of infection [247]. These issues can be addressed using a flexible platform called Coordination Chemistry. The antimicrobial functionality of metal-ligand structures is inherent, and their ability to release antibiotics and antiviral agents in a controlled fashion stabilizes unstable therapeutics and activates them in a targeted fashion or environment [248]. They can be rationally adjusted by their modular assembly, enabling stability, permeability, and drug-carrier interactions to be tuned within bacterial, fungal, and viral environments. The following subsections address modifications to antimicrobial and antiviral therapeutic designs, as coordination-based platforms are redesigned.

Intrinsic antimicrobial activity of metal-ligand complexes

Metal-ligand complexes are usually antimicrobial, and no pharmaceutical agents have been added to them [249]. An explanation for this natural bioactivity is that some metal ions, especially silver, copper, and zinc, disrupt microbial physiological activity through their combined actions. The broad-spectrum bactericidal activity of silver complexes is attributed to their binding to thiol-containing enzymes, which disrupt membrane integrity, induce oxidative stress, and inhibit DNA replication [250]. Ligands such as polyphenols, imidazoles, and carboxylates influence solubility, stability, and cellular uptake. The rapid release of Ag⁺ from coordination structures reduces its toxicity in host tissue and maintains microbicidal concentrations at this site [251].

Copper complexes can also cause redox-mediated toxicity. The redox reaction between Cu²⁺ and Cu⁺ generates ROS and disrupts microbial membranes, proteins, and nucleic acids [252]. Moreover, copper coordination systems enhance Fenton-like responses in the presence of microbes, thereby increasing the oxidative stress [253]. Zinc complexes are less active but moderately active in terms of antibacterial properties. They are characterized by high biocompatibility, which is why they can be used in chronic or topical applications [254].

These metal-ligand complexes may be incorporated into hydrogels, coatings, and nanoparticles and integrated into the surfaces of wounds, implants, and tissue scaffolding such that they can exhibit the continuous antimicrobial activity of these surfaces [255]. The reduction in reinfection and biofilm formation, along with systemic exposure reduction, is effectively supported by long-term antimicrobial release that is promoted via coordination [256].

CPNs and MOFs for antibiotic delivery

Nanoparticles of MOFs and coordination polymers have proven to be universal vectors for the delivery of antibiotics. They have porous or extended architectures that can encapsulate antibiotics, such as vancomycin, ciprofloxacin, tetracyclines, β-lactams, and aminoglycosides. This type of encapsulation protects agents against enzymatic destruction and increases their diffusion to dense bacterial biofilms and therapeutic retention in the foci of infection [257].

Zincimidazolate structures, including ZIF-8, can be rapidly degraded in acidic environments commonly found in infected tissues and thus can be released in a microenvironment-sensitive manner [258]. Inflammatory processes or bacterial metabolism lead to an acidic pH that triggers the disassembly of ZIF, which causes the targeted release of antibiotics where they are required [259]. Additional benefits are provided by iron-based MOFs and CPNs, which have intrinsic redox properties and provide oxidative stress that can increase the effectiveness of antibiotic treatment [260].

The surface functionalization of these frameworks also increased their targeting. For example, ligands containing mannose, chitosan, and peptides that resemble bacterial adhesins bind to bacterial membranes, biofilms, and receptors that are selective for infections. These specific carriers produce better biofilm penetration and reduce side effects on the commensal microbial flora [261].

Overcoming biofilm barriers through coordination platforms

Biofilms pose significant therapeutic problems owing to their high-density extracellular matrix, decreased metabolism, and antibiotic resistance [262]. Coordination-based nanocarriers are excellent for addressing these issues. Their small nanoscale size and modifiable surface chemistry support diffusion across biofilm layers, whereas redox-active metals cause local oxidative stress, thereby disrupting the extracellular polymeric network [263].

Some MOFs release metal ions that react with components of the biofilm matrix, thereby affecting its structural integrity [147]. For example, iron-polyphenol coordination platforms can enter biofilms and generate ROS to break cross-links between polysaccharides. These coordination system structures are modular and facilitate the co-delivery of dispersal agents, quorum-sensing inhibitors, and antibiotics, enabling a holistic approach to eliminate biofilms [264].

Coordination-driven delivery of antiviral agents

The intracellular nature of viral replication is highly problematic in antiviral therapy because it is characterized by a high rate of mutation and immunological escape and, in many cases, low drug stability. The stabilization, protection, and targeted delivery of antiviral therapeutics, including nucleoside analogs, small-molecule inhibitors, peptides, and nucleic acid therapeutics, are facilitated by coordination chemistry [265].

Lanthanide and transition-metal supramolecular cages serve as internal cages capable of encapsulating hydrophobic antiviral agents, thereby increasing their solubility and cellular uptake. These structures help to achieve controlled release and ensure antiviral activity without undesired interactions [266]. In addition, labile or hydrophobic antiviral drugs can be enclosed in metal–ligand frameworks to prevent degradation during circulation [267].

Some coordination complexes exhibit direct antiviral activity. The presence of complexes of both gold and ruthenium in viral proteins or nucleic acids has been reported to inhibit viral entry, replication, or transcription. Their inherent photophysical properties enable photoactivated antiviral effects and spatiotemporal regulation of viral inhibition [268].

Metal-ligand platforms for RNA and DNA antiviral therapeutics

Nucleic acid-based antiviral therapies, such as siRNA-, antisense oligonucleotide-, and clustered regularly interspaced short palindromic repeat (CRISPR)-based therapies, require stable delivery vectors that prevent nuclease degradation and facilitate cellular delivery [269]. The construction of these carriers is based on coordination chemistry. Interactions between metal ligands and nucleic acids offer natural binding sites in the form of condensable, stabilizable, and protective phosphate oxygen atoms. This coordination can shield nucleic acids against serum nucleases, in addition to facilitating their translocation to cellular membranes [270]. MOFs have demonstrated specific usefulness in encapsulating siRNA and CRISPR elements. The pore structure shields the genetic cargo until it degrades under endosomal conditions [271, 272].

Zinc, magnesium, or calcium ions can be coordinated by hydrogel polyplexes of metal-ligand complexes containing histidine, imidazole, or catechol moieties to form stable RNA/DNA therapeutic complexes [273]. The dissociation of metal-ligand bonds, which varies with the pH or redox conditions present in the cytosol, is not only required to release therapeutic nucleic acids but also at the appropriate intracellular site.

Coordination systems for viral reservoir targeting and immunomodulation

Viruses maintained in cellular reservoirs are latent, rendering them unsuitable for standard therapeutic modulation [148]. Coordination platforms have been engineered to target these viral reservoirs via receptor-mediated uptake, metal-affinity binding to viral proteins, or pH-sensitive release in immune cell compartments [274].

Moreover, coordination systems can control immune responses. Oxidative stress induced by metal complexes can also enhance antigen presentation, and lanthanide-containing systems can be used to track antiviral immune responses in real time. CPNs can deliver antiviral drugs and immunomodulators simultaneously, resulting in synergistic antiviral activity [275].

Summary and perspectives in antimicrobial and antiviral coordination therapies

Coordination chemistry provides a powerful and flexible system to deal with infectious diseases. Coordination-based carriers are ideal next-generation antimicrobial and antiviral agents because of their inherent antimicrobial properties, responsiveness to changes in the microenvironment, enhanced biofilm penetration, nucleic acid stabilization, and synergistic catalytic action. They can be rationally designed to provide systems tailored to pathogens, infection sites, and mechanisms of therapy, as well as modularity and tunability [276].

Considering the increasing problem of bacterial resistance and the dynamic nature of viral threats, coordination-based platforms offer a structurally superior and mechanistically diversified repertoire of responses to global infectious disease problems [277]. Future developments are expected to be achieved through a combination of coordination systems, immunotherapeutics, genetic antivirals, and diagnostic imaging devices, which will help develop intelligent, responsive, and personalised anti-infective therapies [278].

Coordination chemistry for gene and protein delivery

Overview of metal-ligand approaches to biomacromolecule delivery

The application of gene and protein therapies requires delivery systems capable of protecting fragile biomacromolecules from enzymatic degradation, facilitating cellular entry, navigating intricate endocytic and trafficking pathways, and controlling release in specific subcellular environments. Conventional polymeric and lipid-based carriers do not always have the structural definition, environmental responsiveness, or stability required to satisfy these requirements [73]. In coordination chemistry, there is a flexible framework for resolving these challenges. Interactions between the metal and ligands stabilize nucleic acid phosphate backbones, which have very high charges, maintain the protein structure, and allow the formation of structures that dissociate in response to stimuli. As a result, systems based on coordination offer a molecularly adjustable method for efficient and safe delivery of genes and proteins [279].

Metal-ligand interactions with nucleic acids

Nucleic acids provide wide coordination sites for phosphate oxygen atoms, nucleobase nitrogen atoms, and donor-rich grooves. These sites are bound by multivalent metal ions, including magnesium, calcium, zinc, iron, and cobalt, which allow the condensation of DNA and RNA into nanoscale particles [280]. These particles have greater resistance to nuclease degradation and are more readily taken up by cells. Condensation occurs through coordination to alleviate the electrostatic repulsion between nucleic acid strands, forming compact structures that are more stable in physiological media [281]. The interaction between metals and ligands plays a key role in endosomal escape, which is a significant obstacle to the successful delivery of genes. The ligands, imidazole, histidine, and polyamine derivatives, are protonated in acidic endosomes; hence, a buffering effect destabilizes the endosomal membranes. These ligands bind to metal ions to form dynamic crosslinks that dissociate in response to pH changes, thereby allowing nucleic acids to be released into the cytosol [282].

Coordination-based nucleic acid delivery systems can incorporate targeting ligands, nuclear localization sequences, or enzymatically responsive components, and as such, provide multi-tiered control of gene delivery pathways. This ability to accurately tune the metal identity and ligand structure enables optimization of the condensation strength, release kinetics, and intracellular biodistribution [283].

MOF-based carriers for CRISPR, siRNA, and other gene editing systems

Another category of vectors becoming highly promising genetic therapeutic vectors is MOFs, owing to their high porosity, structural flexibility, and ability to incorporate macromolecules without disrupting their biological function when placed in the systemic circulation. These dismemberments enable the release of encapsulated genetic material under physiologically relevant acidic endosomal conditions [284].

To facilitate evasion of the endosomal membrane, imidazole or histidine is incorporated into the ligands to provide proton-responsive properties. MOFs composed of iron and zinc can degrade, releasing CRISPR components into the intracellular environment in response to reductive or acidic conditions, but may also offer catalytic or imaging properties. In addition, MOFs can be designed to enable co-delivery, in which two therapeutic agents, one engineered to perform gene editing and the other a small molecule, can interact synergistically, such as by consistently knocking down a gene or treating a disease [279].

MOFs exhibit crystalline and tunable catalytic properties. They can be easily used to generate a uniform distribution of pore sizes and high loading capacity, and to control the release profile, all of which are desirable attributes for novel gene delivery agents. They can be coordinated, covalently coupled, or biomimetically coated to target a specific tissue or cell type [285].

Coordination complexes and supramolecular cages for protein stabilization and transport

Proteins are vulnerable to environmental factors that may cause denaturation, aggregation, and degradation. The field of coordination chemistry offers several approaches to stabilize protein structures and transport them into biological contexts. Confined SCCs, metallocages, and polyhedra can confine single protein molecules or small protein complexes without denaturing their tertiary structures [286]. These cages provide defenses against harsh environmental factors, steric hindrance, and proteolytic degradation. The release of proteins is activated by ligand exchange, pH-dependent dissociation, or redox-dependent structural alterations, thus allowing fine regulation of protein presentation [78].

Metal-ligand hydrogels can be used as multifunctional vectors for protein delivery, in which metal-binding groups such as catechol, histidine, or carboxylate on polymer chains coordinate with metal ions to create networks that entrap growth factors, cytokines, and enzymes. These hydrogels maintain the protein structure and allow sustained or pulsatile release, depending on the dynamics of the metal-ligand crosslinks [287]. They are specially designed for use in regenerative medicine and wound healing, as well as in localized immunomodulation, because their tissue-like mechanical properties and injectability allow their use in these applications [106].

Efficiently coordinated encapsulation strategies inhibit the immunogenic unfolded state of therapeutic proteins and increase their circulation time by covering surface epitopes [288]. This is especially important for therapeutic enzymes, antibody fragments, and engineered proteins whose tertiary structures are sensitive [289].

Endosomal escape and intracellular trafficking enabled by metal coordination

The entrapment of genes and proteins in the endosomal compartments is a significant impediment to the intracellular delivery of mRNA and genes [290]. Coordinated carriers can address this problem in several ways. Metal center-coordinated protonation-sensitive ligands serve as buffering agents in acidic endosomes, causing osmotic swelling that breaks endosomal membranes. Metals that respond to redox reactions, including iron and copper, mediate endosomal escape, where ROS are produced, leading to membrane destabilization [291]. Moreover, the loss of carriers due to pH- or redox-controlled ligand dissociation in endosomes may also lead to rapid structural collapse of the carrier, resulting in the release of cargo into the cytosol [292].

When a phagocytosis event occurs and genetic material is absorbed into the cytosol, special coordination systems may aid in the localization of the nucleus [293]. Metal complexes that can intercalate DNA and coordinate nuclear proteins can increase the nuclear internalization of gene-editing systems or plasmid DNA [294]. The use of atomic localization sequences or metal-binding peptides also helps to target therapeutic macromolecules at the desired location of action [295].

Hybrid coordination platforms for co-delivery of genes, proteins, and small-molecule drugs

Coordination chemistry can accommodate a wide range of ligands and functional molecules, enabling the creation of hybrid platforms that facilitate the co-delivery of genes, proteins, and small-molecule drugs [279]. For example, MOFs with large pore volumes can absorb nucleic acids, simultaneously coordinating small molecules at the metal nodes, or trap proteins within the framework. In addition to capturing chemotherapeutics inside hydrophobic pockets, CPNs can electrostatically bind to nucleic acids. In addition, growth factors and nucleic acids can be released from metal-ligand hydrogels, which stimulate tissue regeneration [296].

These co-delivery systems resulted in synergistic therapeutic outcomes. One gene-editing agent can silence pathways linked to drug resistance, whereas other chemotherapeutic agents induce cytotoxicity. Similarly, a therapeutic protein can regulate immune reactions, whereas antiviral nucleic acids can suppress viral replication [297]. The structural coherence required to combine these varied mechanisms into the same carrier is provided by coordination chemistry.

Design considerations for safe and effective biomacromolecule delivery

The success of coordination-based gene and protein delivery systems depends on careful manipulation of the stability of the metal-ligand complex, cytocompatibility, biodegradability, and release kinetics. The stability of the complexes (excessively high or too low) can prevent their release or retention in tissues and vice versa [166]. The choice of metals should avoid cytotoxicity, especially redox-active metals, which may generate ROS at undesired sites. The ligand design should facilitate biocompatibility, avoid sensitization by the immune system, and facilitate clearance after cargo release [298]. By balancing these factors and exploiting the modularity of metal-ligand interactions, coordination-based systems can be used to safely and effectively deliver gene-editing tools, therapeutic proteins, and nucleic acid-based medicines [299].

Outlook for coordination chemistry in genetic and protein therapeutics

The development of gene and protein therapies is expected to show that coordination chemistry plays a revolutionary role in their evolution. Its ability to stabilize biomacromolecules, be transported intracellularly, and activate multiple stimuli and co-delivery makes it one of the most unique molecules to meet the requirements of precision genetic medicine [300]. Further improvements in the performance and safety of these systems will be achieved by continuing ligand design, biomimetic coordination environments, and hybrid materials. With the development of gene editing and protein therapeutics, extending to oncology, infectious disease, neurology, and regenerative medicine, coordination-based delivery platforms will play an even more pivotal role in obtaining safe and effective clinical outcomes [301].

Hybrid and multifunctional coordination systems

Overview of hybrid coordination architectures

Hybrid coordination systems represent a new category of therapeutic systems that combine the structural complexity of metal-ligand chemistry with the functional diversity of organic polymers, inorganic nanoparticles, biomolecules, and natural matrices [302]. Coordination bonding between organic polymers and inorganic nanomaterials creates hybrid platforms with greater multifunctionality, stability, and synergistic therapeutic efficacy (Fig. 8), allowing the development of multifunctional nanoparticles [303]. The limitations of single-component systems do not constrain these architectures, as they combine multiple functional areas into a single structure [304]. Table 6 provides an overview of the most significant categories of hybrid and multifunctional coordination platforms and their compositional aspects, functionalities, stimulus-responsive dynamics, and therapeutic uses.

Fig. 8.

Schematic of hybrid coordination nanoplatforms with organic and inorganic materials. Organic nanoparticles (liposomes, micelles, dendrimers, PLGA, and chitosan) and inorganic nanoparticles (gold, silver, magnetic, silica, and quantum dots) are used to form hybrid structures, which trap several therapeutic agents, allowing them to be held at a stable level, circulate more easily, and achieve multifunctional and multistimuli-responsive drug delivery [303]

Table 6.

Hybrid and multifunctional coordination platforms: composition, functional integration, and therapeutic utility

Hybrid platform type	Key components	Coordination interaction	Structural characteristics	Stimuli-responsive features	Therapeutic/diagnostic functions	Advantages	Limitations	Representative applications	Notes	References
Polymer–Metal Hybrid Nanocarriers	Polymers (PLGA, PEG, PVP), Fe³⁺/Zn²⁺	Metal–ligand crosslinking	Flexible polymer core with dynamic metal junctions	pH, redox	Controlled drug release	Mechanical tunability, biocompatible	Polymer oxidation possible	Chemotherapy, protein delivery	Good for scalability	[305]
MOF–Polymer Composites	UiO-MOFs, ZIF-8 with PEG/PEI	Coordination + covalent grafting	Crystalline porous framework with polymer shell	pH, enzymatic	Sustained release, targeting	Reduced aggregation, enhanced stability	Complex fabrication	Cancer therapy, gene delivery	Improved colloidal stability	[51]
Lipid–MOF Hybrids	Liposomes + MOFs	Metal affinity to phosphates	Lipid membrane enclosing MOF cores	pH, enzymatic	Drug encapsulation + fusion delivery	High biocompatibility, cell-membrane fusion	Lipid layer instability	Oncology, vaccines	Enhances endosomal escape	[306]
Biomolecule–MOF Hybrids	Peptides, proteins, and DNA with metal clusters	Bio-coordination to metals	Biofunctional surface or internal loading	Enzyme-responsive	Targeting, immune modulation	High specificity	Sensitive to proteolysis	Targeted delivery, immunotherapy	Mimics natural systems	[307]
Metal–Inorganic Nanohybrids	Fe₃O₄, AuNPs, silica + metal nodes	Metal–organic anchoring	Hybrid inorganic cores + metal coordination shell	Magnetic, NIR	PTT, PDT, imaging	Strong external-field response	Clearance issues	MRI-guided therapy	Enables hyperthermia	[125]
Hydrogel–MOF Hybrids	Metal-crosslinked hydrogels + MOFs	Coordination crosslinking	3D hydrogel networks with embedded MOFs	pH, redox	Local sustained release	Injectable, self-healing	Limited systemic delivery	Regenerative medicine	Ideal for localized depot	[308]
Protein–Coordination Cages	Proteins + Ru²⁺, Zn²⁺ cages	Metal–protein interface binding	Encapsulation of single proteins	pH, redox	Protein stabilization	Protects the tertiary structure	Dilution instability	Enzyme replacement therapy	Excellent for fragile proteins	[309]
DNA–Metal Supramolecular Assemblies	DNA scaffolds + metal complexes	Metal–nucleobase coordination	Programmable nanoarchitectures	pH, light	Logic-gated release	High programmability	Complex synthesis	Gene therapy	Enables digital-like logic	[310]
Polymer–Metal–Inorganic Ternary Hybrids	Polymers + metals + inorganic cores	Multiple coordination modes	Multilayered nanostructures	pH, light, redox	Multimodal therapy	Highly multifunctional	Formulation complexity	Triple-modality oncology	Next-gen multimodal carriers	[311]
Biomimetic Membrane–Coated MOFs	Cell membranes + Zr⁴⁺/Fe³⁺ MOFs	Coordination + membrane adhesion	MOF core wrapped with natural membrane	Enzymatic, immune-modulated	Immune evasion + targeting	Long circulation	Membrane variability	Cancer immunotherapy	High biological stealth	[285]

They can be rationally designed to display simultaneous controlled drug release, targeted delivery, imaging properties, and catalytic and mechanical versatility. The coordination-chemistry design of modularity enables an unproblematic combination of different components and provides a more expansive design space for precision therapeutics that respond to complex biological settings.

Integration of coordination chemistry with polymeric nanocarriers

Synthetic polymers exhibit mechanical flexibility, biocompatibility, and controlled degradation profiles, which make them ideal candidates for coordination chemistry [30]. Dynamic crosslinking, structural stability, and stimulus-responsiveness in polymeric systems are achieved through the integration of metal-ligand interactions [312]. For example, polymers with catechol, imidazole, pyridyl, or carboxylate functional groups can bind iron, zinc, or calcium ions to create networks that are stable under physiological conditions but dissociate under acidic or reductive conditions [313].

Polymeric nanoparticles with metal coordination motifs have a high drug-loading capacity, flexible surface functionalization, and controlled release kinetics. Crosslinking enhances mechanical integrity, reduces burst release, and simplifies the introduction of numerous therapeutic agents, all of which are possible through coordination [314]. Additionally, reversible coordination interactions provide self-healing capabilities when shear-thinning and injectable regimes are applied, which is beneficial for local therapy and tissue repair.

Organic-inorganic coordination hybrids

Hybrid coordination systems that combine organic carriers with inorganic nanomaterials have synergistic therapeutic and diagnostic potential [70]. For example, metal-organic structures coated with lipid bilayers exhibit increased colloidal stability and improved membrane fusion properties. MOF composites based on silk fibroin create biodegradable scaffolds that degrade enzymatically, thereby releasing therapeutics in a regulated manner [315]. Moreover, graphene oxide conjugated to metal ions forms hybrid structures that enable photothermal conversion, drug loading, and catalytic activity [316].

Different imaging modalities, such as magnetic targeting, hyperthermia, and optical activation, have been enabled by the incorporation of inorganic nanostructures, including Au nanoparticles, Fe oxide nanoparticles, silica nanoparticles, and quantum dots [317]. Coordination bonding serves as a glueing system that holds these varied elements together, enabling the creation of stable, sensitive hybrid systems. Such organic-inorganic integration is paramount for the formation of multifunctional nanoplatforms incorporating multiple therapeutic pathways [318].

Biomolecule-assisted and bioinspired coordination systems

Biocompatibility, along with intrinsic functionality and the capacity to interact with biomolecules such as peptides, proteins, nucleic acids, and polysaccharides, underpins the overall performance of coordination systems. Their combination enhances the specificity for targeting, decreases immunogenicity, and interacts with biological signaling pathways [319].

Programmable self-assembly and sensitization to biological cues are achieved using bioinspired domains, such as catechol-mediated adhesion, zinc finger-like foldamers, peptides containing histidine, and metalloprotein-like binding domains [320]. DNA coordination produces dynamic scaffolds that can release drugs in a logic-gated fashion, and tissue-specific receptors with high affinities regulate the peptide conjugates [321]. The Hyaluronic acid, which is complexed with metal ions, binds to CD44-expressing tumor cells, thus making it more selective for uptake [322].

The bioinspired combination of coordination motifs will enable the development of hybrid systems that mimic the behaviour of biological systems and, as such, enhance therapeutic specificity and minimise off-target interactions.

Multi-stimuli responsiveness in hybrid coordination platforms

Hybrid coordination structures are composed of multiple stimulus-responsive processes that work together to efficiently navigate complex physiological conditions. These systems include those with acidic pH, redox gradients, enzyme expression profiles, light exposure, and magnetic fields [312]. For example, a MOF-polymer hybrid can contain pH-sensitive metal-ligand cross-linkages, redox-labile cross-linkers, and gold nanoparticles that can be activated with photothermal energy. When acidic or reductive conditions develop upon accumulation in diseased tissues, some degree of framework degradation can occur, which in turn results in light-induced release of other therapeutic agents [306, 323].

Metal-ligand hydrogel systems containing iron-oxide nanoparticles can respond to changes in pH via coordination dissociation and simultaneously enable magnetic targeting or hyperthermia [324]. Such multi-stimulus systems can be activated sequentially, thus allowing precise control of therapeutic operations such as pre-accumulation, microenvironment sensing, structural remodeling, and externally activated final release [325].

Theranostic hybrid coordination systems

Theranostic systems are therapeutic and diagnostic systems that enable the real-time monitoring of drug delivery, therapeutic activation, and disease progression on a single platform [326]. Metal centers offer intrinsic imaging, including gadolinium for MRI; europium or terbium for luminescence; iron and copper for T₂-weighted MRI and PET imaging; and gold for CT enhancement [75]. Hybrid coordination structures allow the simultaneous incorporation of metal-based imaging agents and therapeutic cargos in an organized responsive environment.

Gadolinium MOFs can co-encapsulate chemotherapeutics, enabling MRI-guided chemotherapy. MOF hybrids with gold also enable CT imaging for PTT. Iron-based polycoordination nanoparticles allow MRI imaging of drug delivery and the catalytic production of ROS, which can be used in CDT [327]. Visualization and quantification of therapeutic performance lead to clinical precision, early detection of treatment response or failure, and adaptation of treatment strategies.

Hybrid coordination systems for synergistic multi-drug delivery

Co-delivery of different classes of therapeutic agents (i.e., proteins, small molecules, nucleic acids, and photosensitizers) is enabled by hybrid systems [328]. Coordination nodes can bind to a single type of therapeutic molecule, and polymeric or lipid components can be used to encapsulate other agents. This multi-compartment design also allows controlled, sequential, or simultaneous release, which is specific to multi-agent therapy regimens.

For example, a metal-organic structure could potentially entrap doxorubicin into its pores and assemble cisplatin prodrugs at its metal nodes [122]. Similarly, metal–phosphate polymer nanoparticles can carry siRNA and hydrophobic chemotherapeutics in an organic polymeric structure [329]. These multi-agent systems can effectively target tumor heterogeneity, circumvent drug resistance, and exploit synergistic therapeutic pathways.

Design considerations for hybrid coordination platforms

Hybrid coordination mechanisms must be cautious regarding the compatibility of the parts to be assembled. The kinetic stability of the interactions between ligands and metals should be ensured without affecting the activity of the polymeric or biomolecular constituents. The pathways of degradation proceed via the generation of non-toxic products, and the choice of ligand, the density of cross-linking, and environmental sensitivity determines the release profile. Moreover, surface chemistry should foster colloidal stability, immune evasion, and targeted endocytosis, while avoiding disruption of stimulus responsiveness.

Future studies should consider scalability and reproducibility. Microfluidic synthesis, biomineralization-inspired assembly, and modular supramolecular design are among the approaches used to develop hybrid systems with consistent compositions and performance, and to translate them.

Outlook for hybrid and multifunctional coordination systems

Hybrid coordination architectures represent a bi-convergence of chemistry, materials science, and biotechnology. These are the future of precision medicine because of the possibility of integrating various functionalities into a single molecularly defined structure (targeting, controlled release, imaging, catalytic action, and drug synergy) [330]. Further advances in ligand design, computational modeling, automation, and bio-inspired engineering are expected to increase the variety and sophistication of these hybrid systems. As these platforms continue to progress to clinical practice, they will be able to assist in individualized, innovative, and exceptionally effective treatment protocols across numerous sectors such as oncology, infectious illnesses, immunotherapy, and regenerative medicine.

Clinical translation and challenges

Overview of translational barriers and opportunities

The variety of drug delivery systems developed with coordination chemistry has been astonishing, about ornate structural studies and exceptionally responsive functions. Nevertheless, a serious issue remains regarding its use in clinical practice after laboratory testing. The clinical environment implies that platforms based on coordination should fulfil high-stability and safety criteria, reproducibility, scalability, and regulatory compliance criteria before being allowed in humans [331]. Linguistic obstacles specific to translation systems that derive their power from coordination require comprehension to accelerate their introduction into therapeutic applications. The following section explores the crucial challenges in the clinical course of coordination-based drug delivery systems, including chemical, biological, manufacturing, regulatory, and economic factors. High-level translational obstacles and new solution directions are shown in Fig. 9 [332].

Fig. 9.

Diagrammatic illustration of Key stability, design, and translational issues at advanced biologic and coordination-based therapeutics. The figure includes gene, cell, and mRNA therapies, as well as protein modalities, including physiological sustainability, metal-free toxicity, immune responses, manufacturing scale, and regulatory networks [332]

Stability and predictability in physiological environments

The main issue in translational research is achieving good performance under physiologically relevant conditions. Systems in which coordination determines stability need to be stable in the systemic circulation and resist early degradation, which is predetermined by pH changes, competing ligands, serum proteins, and changes in ionic strength. For instance, Zn-imidazolate MOFs such as ZIF-8 may undergo rapid degradation under acidic conditions, which is advantageous for endosomal/tumor release but can also lead to premature collapse and burst drug release if not sufficiently stabilized. At the same time, these systems should be sensitive to specific triggers found in diseased tissues, such as acidic pH, high glutathione levels, or enzyme activity, so that they can be activated in a controlled manner.

Ligands, including amino acids, phosphates, nucleotides, and proteins, are found in biological fluids and may compete with the coordination sites [333]. Phosphate ions can displace carboxylate or imidazole ligands in some MOFs, and serum albumin can interact with metal centres, thereby influencing the stability of the complex [334]. This instability primarily arises from competitive coordination, in which phosphate anions bind strongly to exposed metal nodes, promoting ligand exchange or partial framework dissolution, whereas protein adsorption (corona formation) can further accelerate surface-driven degradation and premature cargo release. Recent stabilization strategies include using robust high-valent nodes (e.g., Zr⁴⁺), strengthening linker coordination, and applying protective surface coatings (e.g., polymers or lipid shells) to reduce phosphate/protein access and improve serum stability. It is essential that predictive modeling of the metal-ligand exchange dynamics, combined with in vitro simulations of realistic biological media, be performed to estimate the behavior of stability under clinically relevant conditions [335]. This instability can be alleviated by the design of ligands with high affinity, incorporation of chelating motifs, and steric protection surrounding the metal centers [336].

There is a need for uniformity in behavior among patient groups. Changes in the pH, redox potential, vascular permeability, and enzyme expression require delivery mechanisms that are unaffected by physiological heterogeneity.

Toxicological considerations and long-term biocompatibility

The toxicity of coordination-based therapeutics is a critical issue for their development. Possible harms include the release of metal ions, the accumulation of non-biodegradable substances, the formation of ROS, and reactions with essential biomolecules [337]. Similarly, redox-active Fe- or Cu-based coordination systems can enhance efficacy by generating ROS; however, uncontrolled ROS production and slow clearance of stable inorganic fragments may increase off-target toxicity, underscoring the need for careful design and pharmacokinetic evaluation. Even though the overall safety of metallic materials is usually favorable, they may be toxic because of their inability to be coordinated or quickly removed by body organs such as the liver, spleen, or kidney.

Toxicological assessment is a procedure that involves research on acute and chronic toxicity, immunogenicity, genotoxicity, oxidative stress, and organ effects. Biodegradable coordination systems that break down into nontoxic pieces will reduce long-term risks. The role of ligand chemistry is crucial because potent chelators prevent metal release, and biological ligands render them less immunogenic [338]. The cumulative effects and degradation of the metal ions and products should also be considered during dosage planning.

The distribution and clearance of metals, which should be assessed through long-term pharmacokinetic studies, are necessary to address safety risks and meet regulatory requirements.

Manufacturing, scale-up, and reproducibility

The development of coordination-based nanomaterial currents for clinical use is challenging owing to the complex and sensitive nature of coordination-driven assemblies [133]. Several factors that require strict control during synthesis include pH, temperature, stoichiometry, solvent environment, and reaction kinetics. Even slight perturbations can affect particle size, morphology, crystallinity, or metal-ligand stoichiometry, leading to batch-to-batch dispersion, which is unacceptable in clinical products [339].

To overcome these problems, scalable manufacturing systems such as continuous-flow synthesis, microreactor-based processing, spray drying, and biomimetic mineralization are under development. It is also of utmost importance to standardize post-synthetic modifications such as ligand exchange, polymer coating, or targeting ligand conjugation. Analytical procedures must be dependent on particle size distribution, crystallinity, ligand density, metal content, and cargo encapsulation performance. Stability is required to ensure predictable pharmacokinetics, safety, and therapeutic performance between batches.

Immune recognition and biological clearance

Coordination-based nanocarrier interactions with the immune system are crucial for calculating circulation time, biodistribution, and therapeutic effectiveness. These processes include opsonization by serum proteins, complement activation, and macrophage uptake in the mononuclear phagocyte system, which may lead to their rapid elimination in the circulation. The immune response to these nanocarriers depends on the size, shape, charge, hydrophobicity, and availability of specific ligands or metal centers in the carriers [340].

PEG (surface modification), zwitterionic (surface) coating, and biomimetic cell membrane cloaking have demonstrated the ability to reduce immune detection and significantly increase the circulation time. However, these modifications must not compromise the metals’ stability as ligands or stimuli-responsive characteristics [341]. The complex nature of the interactions between the immune system and nanomaterials is demonstrated by the phenomenon of accelerated blood clearance observed upon the repeated administration of PEG. As a result, the design of surface chemistry, together with global immunological assessment, is key to effective clinical translation.

Regulatory ambiguity and approval pathways

Coordination-based therapeutics is a highly interdisciplinary field that includes pharmaceuticals, biologics, and medical devices, making it difficult to define and regulate them [342]. Regulatory authorities must solve problems peculiar to coordination systems, such as the stability of metal-ligand bonds, degradation mechanisms of multi-component structures, metal pharmacokinetics, and analytical descriptions of nanoscale structures.

Regulatory frameworks require an in-depth assessment of the production process, product consistency, biodistribution, toxicity, and long-term safety. It is necessary to establish uniform methods for determining metal stability, degradation profiles, and metal release. Initial work with regulatory bodies can simplify the situation by classifying and expediting the approval processes. Collaboration among chemists, engineers, clinicians, and regulatory scientists is necessary to close knowledge gaps and accelerate clinical development [343].

Variability in patient-specific microenvironments

Therapeutics based on coordination are sensitive to microenvironmental stimuli. However, physiological indicators (pH, redox potential, enzyme activity, vascular density, and immune status) vary significantly among patients and at various disease stages. These differences can affect the drug release kinetics, carrier stability, biodistribution, and overall therapeutic efficacy [344].

Acidity, hypoxia, and glutathione levels in tumors vary and affect the behavior of pH- and redox-sensitive carriers. Diversity is exhibited in enzyme expression profiles and in the immune status of infections, thereby affecting enzyme-responsive delivery processes. The diversity of patients also requires the establishment of flexible delivery systems or the use of customized treatment plans determined by biomarker profiling and imaging.

Adaptive therapy and real-time monitoring are enabled by adding diagnostic capabilities to the coordination platforms. Individualized tracking of dosage, trigger sensitivity, or delivery schedule could result in improved clinical performance [345].

Economic and infrastructural considerations

The complexity of production, use of special materials, demand for sophisticated characterization, and cold chain storage may increase the cost of production of coordination-based therapeutics to a greater extent. Scalable synthesis, simplified formulations, and compatibility with the current healthcare infrastructure are conditional on the economic viability of clinical adoption [346].

This may require special equipment and strict quality control processes because hybrid coordination architectures involving more than one component are highly specialized. To make this process commercially viable, there is an urgent need to embrace cost-effective production approaches, including green synthesis, solvent reduction, and automated processing. Through concerted action among academic researchers, industry stakeholders, and regulatory authorities, coordination-based platforms can be developed into products readily available in the medical sphere.

Outlook for clinical advancement

Despite these challenges, there have been marginal changes in coordination systems for drug delivery through incremental changes in clinical practice [347]. New trends in ligand design, computational modeling, predictive stability of metal-ligand interactions, and scalable fabrication techniques have been used to address long-standing challenges [348]. Adaptive precision medicine is achieved through the integration of the imaging and diagnostic properties of therapeutic systems, and hybrid materials have been made biocompatible and effective.

To build good safety profiles, manufacturing reproducibility, and responsiveness, future clinical translation should be characterized by the sensitive nature of regulatory processes to the complexities peculiar to coordination chemistry. Long-term interdisciplinary innovation can lead to radical change in clinical practice across oncology, infectious diseases, gene therapy, and regenerative medicine, with the assistance of coordination-based therapeutics.

Future outlook

Emerging directions in coordination-driven therapeutic design

Recent progress from 2021 to 2025 highlights rapid evolution in coordination-driven therapeutic systems, particularly in stimuli-responsive design, multi-functional platforms, and clinically oriented engineering strategies.

Coordination chemistry plays an essential role in the design and development of advanced drug delivery systems. Their natural modularity and molecular precision enable the construction of architectures that operate in complex biological settings and dynamic disease conditions [294]. Several disruptive trends have emerged as the discipline continues to evolve. These trends are indicative of advances not only in coordination chemistry but also in computational modeling, materials science, synthetic biology, and biomedical engineering. These results indicate the possibility of a future in which coordination-based therapeutics could be integrated into precision medicine.

AI-guided design and adaptive biomimetic platforms

The design of coordination-based drug delivery systems will be transformed by artificial intelligence and machine learning. The ample chemical space of the potential metal-ligand interactions, framework topologies, and hybrid structures is larger than that explored experimentally. Modeling powered by AI can help predict metal-ligand binding energies, stability of frameworks in the biological environment, degradation, and responses to stimuli quickly [295].

Machine learning programs can be used to identify the most effective ligand structures, predict biologically important pH and redox behavior, and model nanoparticle pharmacokinetics [296]. It is possible to screen candidate architectures using deep learning models trained on structural data to identify architectures with desired biocompatibility and therapeutic properties. Such computer capabilities save significant time in discovery cycles and support rational design plans that match chemical stability to biological demands [297].

Inspired by natural metalloproteins, metalloenzymes, and metal-binding biomolecules are highly desirable. They exhibit remarkable specificity, modularity, and responsiveness, which occur in biological systems and are effectively reproduced in synthetic coordination carriers [300]. Zinc finger domains, heme-binding pockets, and catechol-based adhesion motifs are bioinspired ligands designed to provide precise control over binding properties and biological compatibility [301].

Recent studies have focused on the bio-integration of coordination patterns in cellular or extracellular environments using bio-integrated materials [302]. Such fine examples include metal-ligand hydrogels that mimic the action of the extracellular matrix and MOFs engineered to bind with high specificity to cell-surface receptors. Such a biomimetic methodology enables coordination systems to interface with biological tissues ad hoc, thereby facilitating biocompatibility, targeting, and therapy [303].

One of the rapidly emerging frontiers in medical research is real-time adaptive therapeutics, which can adjust to changes in disease environments. Dynamic ligand exchange, reversible crosslinking, and stimuli-responsive reconfiguration of coordinate systems can alter their behavior in response to changes in pH, oxygen, enzyme activity, or immune interactions [67, 315]. This flexibility is required when disease heterogeneity is high, as in aggressive tumors, chronic infections, and inflammatory diseases.

Feedback processes in next-generation coordination systems might involve activating therapeutic changes in the oxidation state of metals, the presence of ligands, or the integrity of the framework, thereby inducing self-regulation of release. Biosensors on coordination carriers can enable real-time detection of tumor metabolism, inflammatory signals, or microbial activity, thereby enabling direct adaptive release and therapeutic modulation [304].

Multi-metal, multifunctional, and convergence with advanced therapies

In the future, coordination systems will integrate multiple metals with complementary properties to allow logic-gated or hierarchically responsive therapeutic applications. These multimetal platforms can incorporate pH-responsive zinc nodes, iron redox centers, phototherapeutic ruthenium complexes, and imaging-responsive lanthanides into a single platform [297]. These systems may be programmed to release drugs that are responsive to specific combinations of stimuli or to trigger cascades of therapeutic pathways [299].

These multimetal scaffolds enable advanced theranostic capabilities, including MRI contrast, photodynamic therapy, catalytic ROS generation, and targeted drug delivery. Modular coordination interactions represent a significant advance in innovative therapeutic systems that can adapt to evolving disease conditions.

Owing to the broad flexibility of coordination chemistry, it is an impactful integrative system for emerging precision technologies, such as gene editing, immunotherapy, and regenerative medicine. Coordination structures have been described as modular with respect to ligand design, metal selection, and regulated degradability, and can be readily embedded [308]. The most striking feature of these structures is their specific delivery, controlled activation, and programmability at both the molecular and cellular levels.

Gene-editing coordination-based carriers can be programmed to stabilise nucleic acids and promote intracellular delivery, and to deliver genome-editing cargo in response to biochemical signals [309]. Another immunomodulator in immunotherapy uses metal-ligand scaffolds to display antigens, control immune signaling, or deliver immunomodulatory agents in space and time. Coordination polymers and MOFs offer versatile, mechanically robust, degradable, and bioactive surfaces that can be designed to facilitate cell growth, tissue repair, and the topographical delivery of growth factors in regenerative medicine [310].

With these two capabilities and diagnostic imaging, an integrated theranostic platform can provide real-time monitoring of the delivery, activation, and biological outcomes. This convergence enables coordination chemistry to be viewed as a platform for technologies to construct next-generation patient-specific interventions across a spectrum of advanced therapeutic modalities.

Manufacturing scalability and precision medicine vision

The need for scalable manufacturing processes has become increasingly important as coordination-based therapeutics advance toward clinical applications. Next-generation coordination systems should align with industrial practices, maintain batch-to-batch consistency, and employ environmentally friendly synthetic processes. Advances in continuous flow synthesis, microfluidic fabrication, automation of self-assembly, and utilization of green solvent systems have led to the more reliable and environmentally friendly production of complex coordination architectures [305].

To ease the commercialization process, there is a need to standardize fabrication protocols, determine clinically acceptable metal ligand chemistry, and streamline purification and storage strategies. Moreover, the following line of manufacturing can be enhanced by implementing real-time monitoring of assembly processes using spectroscopic or AI-based tools to ensure consistency and quality control.

Coordination-based therapeutics align naturally with the goals of personalized medicine because they can be precisely programmed to exhibit tailored structural features and respond to diverse physiological or pathological stimuli [306]. In the future, patient-specific ligand architecture, metal identity, framework degradability, and targeting using genomic, proteomic, metabolic, and imaging biomarkers are expected to become central applications.

Engineered systems mediate activation and individualized dosing plans and are sensitive to patient-specific microenvironmental parameters such as unique tumor acidity, redox conditions, and enzyme expression. This can be combined with diagnostic imaging, which enables real-time evaluation of therapy dispensation and efficacy, and may be applied to support adaptive treatment plans that may evolve as the disease advances [307].

The future success of coordination-based drug delivery systems depends on technological advancements in multipurpose, dynamic platforms that can address the complexity of human diseases. Coordination chemistry has provided a platform for more efficient, molecular-specific, and sustainable therapeutics through the incorporation of metal-specific behaviour, computational design, biomimetic architecture, multi-stimuli responsiveness, and multi-materials [311].

As interdisciplinary research and the establishment of clinical bases continue to develop, coordination-based drug delivery systems will align with the essential qualities of a new generation of medicine. Their natural versatility, diversity of chemical activity, and applicability across various treatment modalities can revolutionise treatment opportunities in fields such as infectious diseases, oncology, immunotherapy, neurology, and regenerative medicine [312].

Conclusion

The future success of coordination-based drug delivery systems has been linked to the advancement of innovative, multipurpose, and adaptive platforms that can manage the complexity of human diseases. These are coordination-based systems that stabilize fragile biomacromolecules and selectively respond to biological gradients, including pH and redox potential, to generate therapeutic ROS. Further, they encourage photodynamic, photothermal and chemodynamic intervention. They could be administered with small molecules, nucleic acids, proteins, and imaging agents that can synergise with the treatment mechanisms of complex diseases, including cancer, infectious diseases, and inflammatory diseases.

The hybrid coordination architectures expand the functional and operational range of the metal centers, polymers, biomolecules and inorganic nanoparticles in the same space. Such systems are multistimulus-responsive, biocompatible, mechanically robust, and multitheranostic. The overlap of coordination chemistry, immunotherapy, and regenerative medicine highlights the field’s role in complex biomedical biomarkers that transcends traditional pharmacology.

Although these have been accomplished, they have encountered some difficulties in translating their findings into clinical practice. This is very strenuous, considering the sustainability of the physiological media, long-term biocompatibility, metal toxicity, the ability to generate reproducible output, implantation effects, and regulations. Interdisciplinary group work will be relevant to the optimization of ligand design, the enhancement of predictive modelling, the design of scalable and sustainable manufacturing, and the development of routine systems for measuring toxicity and stability.

Coordination chemistry is also regarded as one of the driving forces of future personalised precision medicine. The more time-consuming development of the best coordination structures is more likely to be driven by artificial intelligence and computational modelling. At the same time, biomimetic/adaptive systems have the potential to drive personalized, dynamic therapeutic responses tailored to each patient’s microenvironment. Moreover, multi-metal and logic-gated systems can initiate a new horizon for intelligent therapeutics that can be incorporated into diagnostic, imaging, and therapeutic approaches.

Finally, coordination chemistry offers a single flexible molecular design for drug delivery systems with high precision, versatility, and therapeutic properties. Being the recent tendency in this sphere, coordination-based platforms are likely to be applied not only to the theoretical innovations but also to change the future of the specific, multimodal, and individualized therapies of various diseases.

Author contributions

Kuanbing Chen.Feng Guo.: Conceptualization, Methodology, Writing – original draft; Writing – review & editing.Xin Zhang.Yu Li.: Data curation, Formal analysis; Writing – review & editing.Ying Xuan.Xiaofeng Wang.: Supervision, Writing – review & editing.All authors reviewed and approved the final manuscript.

Funding

Basic Research Project for Universities of Liaoning Provincial Education Department(LJ232410159083; Health Commission of Liaoning Province, “Xingliao Talents Program” Project (XLYC2412088).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.