Design and synthesis of metal–organic cycles/cages (MOCs) and their applications

Supramolecular interactions¹ play a pivotal role in creating intricate and functional molecular assemblies² with increased complexity and enhanced capabilities,³ which ultimately foster the emergence of innovative materials.⁴ A primary method for developing these elaborate suprastructures⁵ involves self-assembly of fundamental molecular building blocks⁶ into purposeful frameworks.⁷ Among the wide range of available self-assembly methods, coordination-driven self-assembly (CDSA)⁸ is an exceptionally efficient synthetic technique. By carefully choosing an appropriate metal ion and meticulously designing ligands, metal–organic complexes (MOCs)⁹ with diverse sizes, shapes, and metal-to-ligand ratios can be generated through CDSA.

Metal–organic cycles/cages (MOCs) refer to precisely characterized, individual molecular entities that form either two-dimensional (2D) or three-dimensional (3D) suprastructures¹⁰ featuring appropriate metal ions through coordination with organic ligands containing designed binding sites. The impetus for utilizing MOCs in biological applications¹¹ lies in their defining characteristics, including the convenience of precisely adjusting the size of the complexes,¹² the ability to choose metal ions of specific dimensions,¹³ their specific coordination geometry,¹⁴ and the straightforward incorporation of vital functional groups through modification before or after the self-assembly process.¹⁵ In this Review, the traditional applications of MOCs in biomedicines; sensors; catalysts; and light-harvesting, patterning, and loading/release systems are discussed. With the development of the MOC field, the applications of MOC-based hierarchical assemblies have been explored. They exhibit excellent properties in smart biomedical materials, cascade light-harvesting systems, dual-mode catalysts, etc. Finally, the latest strategies for the design and preparation of novel MOCs are presented.

MOCs show excellent antibacterial activity against both gram-positive and gram-negative bacteria.^16,17 As shown in Figs. 1(a)–1(c), from triangle to hexagon to prism, the materials all exhibit antibacterial activity through host–guest interactions and combination with GaMOF. Recently, the formation of a mixture of benzodithiazole-based triangles and squares was reported, and the use of pyrene-1-aldehyde (G1) as a guest led to the transformation of the mixture to a guest-encapsulated triangle (G1′ ⊂ MOC1) that could kill Pseudomonas aeruginosa bacteria through synergistic antibacterial activity. G1′ ⊂ MOC1 was found to selectively prevent the biofilm formation of methicillin-resistant Staphylococcus aureus, which was caused by enhanced reactive oxygen species (ROS) generation via host–guest interactions.¹⁸ In addition, the interaction between a pillar[5]arene-modified MOC (MOC2) and a guest improved both fluorescence imaging and ROS production, which enabled accurate tracking of S. aureus-infected sites via fluorescence and efficient execution of image-guided photodynamic inactivation (PDI) of S. aureus. At the same time, this interaction dramatically impeded bacterial persistence through PDI and substantially accelerated the process of wound closure in mice infected with S. aureus. Bacteria can ultimately adapt and demonstrate resilience to nearly all prescribed antibiotic medications. Photodynamic therapy (PDT), which involves minimal development of antibiotic resistance, has emerged as a promising approach for combating bacterial infections.¹⁹ An enhanced PDT approach utilizing tetraphenylethylene (TPE) incorporated with metallacage MOC3 was implemented to minimize ROS utilization by concurrently leveraging gallium-based metal–organic framework rods to suppress bacterial endogenous NO generation, intensify ROS stress, and boost the bactericidal efficacy.²⁰ In addition to the traditional imaging applications, the emission maximum of an MOC can be extended to the near-infrared (NIR)-II region. As shown in Fig. 1(d), MOC4 has the longest maximum emission wavelength of 1005 nm. Both in vitro and in vivo evaluations confirmed that MOC4-loaded nanoparticles have excellent biocompatibility and stability, providing both accurate tumor diagnosis and total tumor elimination via a dual imaging-guided strategy that combines synergistic photodynamic and photothermal therapy.²¹ Another example is MOCs with emission wavelengths spanning from the red to NIR-II region. The prism-shaped metallacage MOC5 exhibits a remarkable fluorescence emission in the second near-infrared (NIR-II) region [Fig. 1(e)]. MOC5 displays an emission maximum at 981 nm. MOC5-loaded nanoparticles exhibit a high absolute quantum yield in the NIR-II region, rendering them highly effective for blood vessel imaging.²² Interestingly, imaging for hypoxia detection was reported, as shown in Fig. 1(f); under hypoxic conditions, the dual-emissive metallacage MOC6 exhibits both blue fluorescence and red phosphorescence, and the red phosphorescence of the metallacage is significantly enhanced, reaching a 48-fold increase, while the blue fluorescence remains largely unchanged.²³ 

Furthermore, in vivo experiments demonstrated that MOC6 nanoparticles (MNPs) enable more precise hypoxia detection, indicating their potential as promising candidates for practical theranostic applications that combine tumor hypoxia imaging and chemotherapy while enhancing the circulation time and tumor accumulation. A radiolabeled and targeted metallacycle heteroleptic cage, MOC7, which targets the somatostatin-2 receptor and incorporates the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator, was produced by Deiser et al. [Fig. 1(g)]. These systems exhibit enhanced functionality and are potential next-generation theranostic agents.²⁴ 

As shown in Fig. 2(a), MOC8 functions as a fluorescence sensor for the recognition of phosphate (PO₄³⁻) in aqueous solutions through a disassembly process and can be used as a fluorescence sensor for visual detection of PO₄³⁻.^25, MOC9 has been employed for the detection of picric acid, exhibiting selectivity over other nitroaromatic compounds, which is attributed to the generation of a ground-state complex and the subsequent resonance energy transfer between picric acid and MOC9 [Fig. 2(b)].^26, MOC10, which has been used as a colorimetric biosensor for H₂O₂, sarcosine, and glucose [Fig. 2(c)], has long-term stability and distinctive peroxidase (POD)-like activity and was developed through a simplified one-step approach, offering ease of use in detection and achieving detection limits of 1.9, 2.3, and 43.0 µM. The conformation plays an important role in tuning the sensor properties of MOCs. The cation selectivity is significantly influenced by the relative size and conformational properties of MOCs.²⁷ Two platinum(II)-based rectangular MOCs, designated MOC11 and MOC12, were prepared. Fluorescence titration analysis revealed that MOC11 preferentially recognizes Na⁺, whereas MOC12 demonstrates a selective affinity for Mg²⁺ [Figs. 2(d) and 2(e)].²⁸ 

By incorporating photosensitizing TPE as faces and Re catalytic complexes as pillars, harmonious integration was achieved in MOC13 [Fig. 3(a)]. The integration of photosensitizers and catalytic complexes leads to the formation of highly organized structures, which enable efficient and directional electron transfer within the MOC, thereby enhancing photocatalytic hydrogen production. In particular, MOC13 exhibits an exceptional photocatalytic hydrogen production rate of 1707 µmol/g h, ranking among the highest values reported for metallacages.²⁹ The heteroleptic metal–organic capsule MOC14 Pd–ZPP(Fe) serves as a cytochrome P450 analog [Fig. 3(b)], enabling multistep C–H oxidative coupling catalysis. This host–guest approach offers the potential to simultaneously introduce diverse functional groups into various enzymes, thus facilitating parallel reactions and achieving diverse catalytic outcomes.³⁰ Chakraborty et al. presented a study on the various chemical transformations of anthrone within distinct water-soluble M₆L₄ cages (MOC15). Upon encapsulation within MOC15, anthrone undergoes dimerization to yield dianthrone [9,9′-bianthracene-10,10′(9H,9′H)-dione].³¹ 

Conversely, when an identical chemical reaction is conducted within the M₆L₄ double-square cage designated MOC16, anthrone undergoes oxidation to produce anthraquinone [anthracene-9,10-dione] [Fig. 3(c)]. Comparable outcomes were observed in a separate set of isomeric aqueous Pd₆ cages, thereby highlighting the influence of the cage geometry on the divergence of synthetic pathways.³¹ Because porphyrin and its derivatives can serve as efficient photosensitizers to generate singlet oxygen (¹O₂), the metal-coordination bonds would further promote the intersystem crossing to give MOC17 good ¹O₂ generation efficiency upon photoirradiation. Based on this, MOC17 was employed to modulate the production of ROS, ultimately enabling their selective utilization in the photocatalytic oxidation of benzyl alcohols [Fig. 3(d)]. Upon irradiation, MOC17 efficiently generates singlet oxygen through excited energy transfer, while its complex facilitates electron transfer, leading to the formation of superoxide anions. The introduction of 4,4′-bipyridine into the complex via coordination with the Zn porphyrin faces of MOC17 and BPY results in the expulsion of fullerenes from the cavities, thereby restoring the capacity for generating singlet oxygen.³² 

MOC18 demonstrates exceptional emissive properties in both solution and solid-state forms, which is attributable to the synergistic effect of coordination bonds and aggregation, which restrain the molecular movements of TPE and consequently mitigate nonradiative decay within these metallacages. Given its remarkably high quantum yield and favorable solubility, MOC18 was applied as a coating on a blue light-emitting diode (LED) bulb, facilitating the production of white LEDs (WLEDs) through phosphor conversion. Upon application of a 3 V bias, vibrant white light was emitted. According to the 1931 Commission Internationale de L’Eclairage (CIE) chromaticity diagram, the color coordinates of this light are (0.28, 0.32), positioning it within the white-light region [Fig. 4(a)].³³ The same group reported hexaphenylbenzene (HPB)-based MOC19 and examined its potential as an energy source for activating nonemissive fluorophores in the solid state. As depicted in Fig. 4(b), HPB-derived deep blue-emissive metallacages serve as antennas, efficiently supplying the necessary energy to excite a nonemissive naphthalimide derivative (NAP), thereby eliciting bright luminescence from NAP in the solid phase.³⁴ The hexagonal MOC20 incorporating TPE and cholesterol displays notably enhanced fluorescence emission and fluorescence quantum yield when aggregated, along with distinct liquid crystal (LC) behavior. The developed light-responsive Förster resonance energy transfer (FRET) system enables versatile orthogonal multimode photopatterning techniques, encompassing holographic, fluorescent, and photochromic patterning, all within a single integrated supramolecular system [Fig. 4(c)].³⁵ Zhang et al. reported a porphyrin-based metallacage, MOC21 [Fig. 4(d)], that hosts polycyclic aromatic hydrocarbons (PAHs). Its binding constant with coronene is 2.37 × 10⁷ M⁻¹ in acetonitrile/chloroform, which is the highest. MOC21 generates singlet oxygen, oxidizing anthracene derivatives to anthracene endoperoxides and releasing guests. Using 10-phenyl-9-(2-phenylethenyl)anthracene, a reversible controlled release system was achieved.³⁶ 

Using MOC22 as the building block, flexible metal–organic materials can be fabricated, as depicted in Fig. 5(a). A Pt MOC film spanning the centimeter scale was assembled in multiple stages and then coated on an N, N′-dimethylated dipyridinium thiazolo[5,4-d]thiazole (MPT)-stained silk fabric.³⁷ Both in vitro and in vivo investigations demonstrated that this combination of a Pt MOC film and MPT-stained silk offers real-time insights into wound infections, enabling prompt treatment via noninvasive methods. Bola-type supramolecular amphiphiles containing MOC23 were formed through host–guest interactions and then self-assembled to form vesicles.³⁸ 

These vesicles exhibit sensitivity to α-amylase and transform back into nanosheets upon the addition of α-amylase due to enzyme-mediated degradation of the cyclodextrins. Moreover, the anticancer drug doxorubicin (DOX) was effectively encapsulated within β-CD-1 vesicles. Upon introducing α-amylase to a β-CD-1 solution, β-CD gradually degraded, losing its complexation ability, thus resulting in the liberation of the drug molecules encapsulated within the vesicles [Fig. 5(b)]. Discrete platinum(II) metallacycle MOC24, containing four cationic pyridinium units, was designed and synthesized, which was able to capture a polycyclic aromatic hydrocarbon guest, a naphthalene flanked with two alkyl chains, into its cavity to form a host–guest complex. By harnessing host–guest interactions and exploiting the reversibility of Pt coordination bonds, a [2]rotaxane was efficiently synthesized. Subsequently, this [2]rotaxane was employed in the development of an efficient light-harvesting system, which significantly extends the application domain of macrocycle-based host–guest systems and serves as an example of a practical approach for synthesizing mechanically interlocked molecules [Fig. 5(c)].³⁹ The MOC25-based [Fig. 5(d)] hierarchical assembly processes, operating in a cooperative fashion, yield hierarchical self-assemblies (HSAs) with organized 2D heteroporous structures characterized by positive charges and specific cation–π stacking motifs. These HSAs serve as dual-mode catalytic platforms, enhancing the performance of both catalytic oxidation and photocatalytic reduction reactions. This enhancement is attributed to the effective dispersion of negatively charged nanocatalysts and the optimized charge separation and transfer processes. Consequently, the catalytic oxidation of 5-hydroxymethyl-2-furfural (HMF) to 2,5-diformylfuran (DFF) achieves a remarkable yield of 81.88%, while the photocatalytic reduction of CO₂ to CO is substantially improved, attaining a conversion rate of 723 μmol g⁻¹ h⁻¹.⁴⁰ 

Nitschke outlined a logical approach for utilizing subcomponent self-assembly to purposely create a heteroleptic cage with a substantial cavity volume (2631 Å³) using simple, commercially accessible initial materials.

This approach begins with an initial step of isolating a tris(iminopyridyl)Pd complex, which then undergoes a reaction with tris(pyridyl)triazine to yield a heteroleptic, cage-like structure known as MOC26.⁴¹ The tris(iminopyridyl) ligand functions as a “stabilizer” to regulate the orientations of the unstable coordination sites on the Pd centers. This novel cuboctahedral structure was found to concurrently bind multiple PAH guests [Fig. 6(a)].

A conformationally adaptable tetrapyridyl ligand was individually combined with three cis-blocked 90° Pd acceptors, each incorporating distinct blocking units. The various conformations of the donor were stabilized by Pd acceptors, which were influenced by the specific nature of the amine unit, ultimately resulting in the production of isomeric Pd barrels (MOC27–MOC29) [Fig. 6(b)].⁴² Zeng et al. synthesized MOC30 and MOC31⁴³ by utilizing coordination-driven self-assembly of triphenylamine (TPA)-based donor molecules with various platinum(II) acceptor units. These metallacages leverage their steric hindrance and curved shape to effectively constrain the free rotation of the benzene rings and prevent π–π stacking in the solid state, thereby successfully suppressing fluorescence quenching and achieving remarkably efficient luminescence [Fig. 6(c)]. A cross-catenane is created in the solid state by the interaction of two position-isomeric Pt(II) metallacages. When these metallacages are dissolved in a solution, they form [2]catenanes, but in a 1:1 mixture, they preferentially form a cross-catenane in the crystallized state. Furthermore, researchers aimed to identify the global minimum structures of three [2]catenanes and further refined their low-energy configurations through density functional theory calculations (MOC32–MOC34) [Fig. 6(d)].⁴⁴ 

MOCs represent a category of nanoscale molecular structures that exhibit unique shapes and sizes and are achieved through the deliberate integration of organic and inorganic ligands during their design and synthesis. To date, the diverse functionalities of MOCs have made them candidates for use in fields such as biology, chemistry, and materials science. MOC cavities enable host–guest interactions to realize conformational changes, which is beneficial for catalysis, sensing, loading, and release. MOC-based assemblies have been used in biomedicine and light harvesting. Novel strategies for MOC design/synthesis laid the foundation for its subsequent application.

This work was financially supported by the National Natural Science Foundation of China (Grant No. 22372055). Y. Sun acknowledges the Henan University Third Level Start-up Fund.

The authors have no conflicts to disclose.

Yuanyuan Li: Conceptualization (equal); Writing – original draft (equal). Fengmin Zhang: Writing – original draft (equal). Yan Sun: Supervision (equal); Writing – review & editing (equal).

The data that supports the findings of this study are available within the article.