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Strategies for binding multiple guests in metal-organic cages 

 

Felix J. Rizzuto, Larissa K. S. von Krbek, Jonathan R. Nitschke* 

University of Cambridge, Department of Chemistry, Cambridge, UK, CB2 1EW 

 

ABSTRACT: The binding of multiple guests by a single entity can lead to new modes of host-guest 

interactions, and thus new applications in catalysis, sensing and other supramolecular areas. With 

the aim of developing modular systems that can promote and adapt to allosteric binding events, this 

review explores current strategies used to bind multiple guests in the central and peripheral 

environments of coordination cages. The structural and functional consequences of multi-guest 

binding will be examined, highlighting the methods by which guest configurations involving more 

than one copy of the same guest, as well as multiple different guests, may be designed. We thus aim 

to provide new methodological insights and tools into the design of new capsules for multiple guest-

specific binding events, towards the development of guest-guest chemistry within synthetic systems. 

 

1. Introduction 

Signal transduction networks in biochemical systems generate event-specific responses in order 

to respond to environmental conditions, and to process information.1,2 Allostery, where the binding 

of one substrate affects the binding of another at a distant receptor site, is an integral part of these 

intracellular cascade processes.3,4 Cooperativity between the components of these allosteric systems 

relies on the three-way structural organisation of the receptor and the two (or more) distinct binding 

substrates, which can require long-range communication within and between cellular compartments. 

It is challenging to engineer similar interactions in abiological systems – structural rearrangement, 

association strength, and guest displacement must be gauged to enable multiple binding events and 

to promote communication between species, as opposed to mutually-independent, or non-

cooperative, events. 

A range of hosts – from small organic ion transporters5 to macrocycles,6-9 organic cages10 and 

cavitands,11,12 gels,13,14 and polymers15 – have been used to study molecular recognition 

phenomena.16 Many of these hosts are capable of co-encapsulating guests: either two of the same 

guest (homotropic binding) or two different guests (heterotropic binding).17-20 Building on the 

foundations of this organic host-guest chemistry, soluble metal-organic cages have also displayed 

the ability to bind multiple guests simultaneously. Owing to the geometries imposed by different 

ligand configurations and metal coordination environments, these assemblies possess immense 

structural diversity. Minor changes in the metal or organic components can lead to major differences 

in structural outcomes, with correspondingly diverse cavity geometries.21-23 Structure prediction is 



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becoming possible through analysis of the symmetries and connectivity properties of both the 

organic and inorganic constituents of cages.21,24  

The ability to tailor the cavities of these capsular complexes has led to diverse host-guest 

chemistry, including the recognition of specific molecular targets, the purification of product 

mixtures,25 and new asymmetric catalysis pathways.26 The rules governing the specificity and 

strength of molecular binding events are nevertheless complex. To expand upon rules discovered 

through serendipity, a series of methods to design guest association have been implemented, ranging 

from simple electrostatic complementary to overall scaffold design and cavity engineering.27,28 

Principles for the design of hosts that are capable of binding multiple guests simultaneously, 

however, have not yet been compiled. The development of such principles could enable the 

expansion of encapsulation phenomena beyond single molecule binding to the stabilisation of 

combinations of guests, and the resulting new properties that molecular clustering may yield.  

In this review we summarise the most successful approaches for promoting the binding of 

multiple guests within coordination cages, with a view towards designing the multiple guest 

recognition properties of metal-organic assemblies. We will focus on methods for improving the 

association strength and cooperativity of guest binding in metal-organic hosts through strategies for 

central guest encapsulation, followed by methods exclusive to the formation of higher-order host-

guest complexes, and finally the applications of these systems beyond allosteric binding regulation. 

 

2. Central guest encapsulation 

2.1 Solvophobic effects 

Although a detailed description of solvophobic effects is beyond the scope of this review, these 

effects are understood to be at work when multiple particles combine to form a single entity – such 

as guests binding to a host – in solution. An entropic penalty is thus incurred, which is 

counterbalanced by both the entropic gain of liberating ordered solvent molecules associated with 

these particles into the bulk solvent, and the enthalpic gain of forming new, favourable interactions 

between liberated and bulk solvent. When complemented by a favourable enthalpy of binding, such 

solvophobic effects can promote binding.29-31 

2.1.1 Aqueous recognition 

The stability and solubility of hosts in water is of paramount importance in promoting the 

binding of multiple guests.32-34 Water is unique among solvents: hydrophobic effects,35,36 inverse 

hydrophobic effects,37 and chaotropic effects38 can all promote high affinity guest binding, either 



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individually or synergically. Other forces, such as hydrogen bonding, ion-dipole interactions and 

cation-π effects, can be magnified in water.39 Cumulatively, these effects act to reduce rates of guest 

exchange between the cavity of the cage and the bulk solvent, and improve guest binding affinity in 

water. 

Water-soluble cages that contain large hydrophobic panels enclosing their cavities have been 

very successful at employing hydrophobic effects to drive guest binding.40,41 As reported by the 

Fujita group, when no guests are present, the water molecules in PdII
6L4 cage 1 pack in a hydrogen-

bonded array, analogous to the arrangement in Ic-type ice (Figure 1a,i).42 The freeing of these water 

molecules from the cavity upon guest binding outweighs the entropic penalty of guest binding. These 

observations were reinforced by quantitative studies by Raymond and co-workers, who quantified 

the degree to which guest binding in water within GaIII
4L6 cage 2 was entropically driven (Figure 

1b).43,44 Similar effects are observed in other polar solvents, whereby solvent liberation drives an 

entropically favourable binding process.45 These effects are akin to those observed in the organic 

hosts originally detailed by Rebek and co-workers.46  

When a water-soluble cage is large, the displacement of water from the cavity, in concert with 

the effects noted above, enable the clustering of molecules internally. Many water-soluble cages 

synthesised by the Fujita group employ large hydrophobic regions to bind two or more guests in 

spherical voids,41,47-49 or stacks of molecules in tubular structures.50,51 Often, these encapsulated 

guests are hydrophobic, providing favourable enthalpic interactions with the interior cage surface 

upon binding (e.g. Figure 1a.ii, more detailed discussion below). This strategy was employed by 

Klajn and co-workers using flexible cage 3 (Figure 1d), originally reported by Mukherjee’s group.52 

When irradiated, the two encapsulated azobenzene guests undergo trans- to cis- isomerisation, 

ejecting one guest in the process.53 Internal guest binding in water is thus a balancing act: a host 

must be hydrophilic enough to be water-soluble, hydrophobic enough to promote binding internally, 

and have a cavity of an appropriate size to hold the required number of guests. 



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Figure 1 | General principles for central guest binding: employing hydrophobic effects (hosts 1-3) and ensuring 

host-guest fit (hosts 4-6). a, Host 1 can bind up to four organic guests simultaneously, aided by the hydrophobic effect 

(Fujita42,48,54). b, The initial binding event in 2 is entropically favourable, whereas exterior binding is enthalpically 

favourable (Raymond44). c-f, A delicate balance of host and guest electronics and size determine the number of guests 

bound within hosts 3-6 (3: Klajn;53 4: Würthner;55 5 and 6: Nitschke56,57). 



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2.2 Size, shape and electronic complementarity 

Promoting a good size and shape match between a cavity and guest is often critical to promoting 

association. A guest that fits too tightly within the host cavity is restricted in its motion within the 

host, leading to an entropic penalty, whereas a guest that fits too loosely will benefit from few of the 

attractive van der Waals contacts that lead to a favourable enthalpy of binding.58 A 55% occupancy, 

corresponding to the average packing coefficient of common organic solvents, was demonstrated to 

be optimal in many cases by Rebek and co-workers.58 

We consider these principles in the context of the well-explored binding abilities of Fujita’s 

cage 1. With a cavity of ca. 480 Å3, 1 is able to bind up to four organic guest molecules 

simultaneously (Figure 1a.ii-iii).48,54 In each case, the maximum number of guests that can fit inside 

1 without significant structural perturbation of the host is observed. Guest binding is driven by the 

hydrophobic effect together with van der Waals interactions between the guests and the electron 

deficient host. These forces work in synergy; as entropy increases due to solvent displacement from 

the cavity, enthalpy becomes more favourable through complementary host-guest contacts. 

Although half of the shell of 1 is open, potentially allowing guests to escape the cavity, favourable 

contacts between multiple guests complement the entropic and enthalpic factors, rendering guest 

binding favourable. 

The importance of size and shape fit between host and guest is exemplified by hosts 4, 5 and 6. 

Würthner and co-workers encapsulated two fullerenes within host 4, framed by electron-deficient 

perylene bisimide units (Figure 1c).55 At first glance, this porous host appears to provide a poor fit 

for two C60 guests; binding was promoted by extensive contact between the extended π-surfaces of 

the host and guests.  

Walled by porphyrin units, host 5 binds three molecules of coronene (Figure 1e).56 The coronene 

guests form a linear stack, likely stabilised by edge-to-face aromatic interactions between the walls 

of the host and the guest edges. No more than three coronene guests can fit inside 5, and only the 

three-guest adduct is observed: aromatic stacking between the guests appears to engender a high 

degree of cooperativity in their binding. In contrast, host 6 can bind up to four molecules of C60 

within its cavity anticooperatively, such that binding is progressively inhibited as more fullerenes 

are bound (Figure 1f).57 The saddled porphyrin walls of this assembly pivot to accommodate these 

guests, maximising inter-guest and host-guest contact to generate encapsulated fullerene clusters. 

This pivoting appears to engender strain as more fullerenes are bound, however, leading to the 

observed anticooperativity. In both cases, close contacts between aromatic cage walls and aromatic 

guests lead to strong binding affinities.  



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2.3 Electrostatics and cage charge 

With few exceptions,59,60 metal-organic architectures have charge associated with the metal ions 

holding them together; typically, metal ions frame the corners of these complexes, defining the 

vertices of polyhedra. These positively-charged hosts are thus able to attract and bind negatively-

charged guests (and vice versa). Electrostatic attraction may even compensate for a poor match 

between cavity size and guest volume, or the entropic penalty associated with guest binding.61,62 

Recent investigations by Flood and co-workers have shown that the strength of guest binding, 

driven by electrostatics, can be modulated by the solvent employed.63 A correlation between the 

solvent dielectric constant and anion binding affinity was identified in an organic host. Investigations 

of the guest binding properties of a lantern-shaped host by Lusby and co-workers have echoed this 

finding in metal-organic cages, deducing that solvent-mediated modulation of the strength of ion-

pairing interactions between cationic hosts and their anions can lead to significant changes in the 

association constants of neutral guests.64 Weakened ion-paring of the host led to an increase in the 

binding strength of the guest, allowing the guest binding affinity to be tailored through the choice 

of counterion. 

While electrostatic attraction aids binding between charged guests and hosts, studies by Sallé 

and co-workers have shown that neutral guests bind best within neutral cages.60 Their work 

compared PdII
4L2

8+ cage 7 to its neutral Pd0
4L2 analogue 8 (Figure 2a.i). Whereas the polycationic 

cage bound coronene with moderate affinity (Ka < 102 M–1), its neutral congener bound guests a 

thousand times more strongly (Ka = 105 M–1). Electrochemical manipulations on guest molecules 

have also shown the redox state, and thus charge, of a guest to effect its uptake and release from a 

receptor.65,66 

Similar strategies can overcome the electrostatic repulsion experienced by two anions binding 

in proximity within a cavity.16 A good fit between the cavity and guest sizes can facilitate multiple 

anion bindings. Host 8 binds two equivalents of B12F12
2–, which sit in optimally-sized pockets at 

either end of the structure (Figure 2a.ii).67 Comprehensive studies by Chifodes, Dunbar and co-

workers have shown that tetramer 9 (synthesised in the presence of a BF4
– template) converts to 

pentameric metallocycle 10 upon binding two SbF6
– anions (Figure 2b).68 The co-encapsulation of 

these two anions is driven by directional anion-π interactions between SbF6
– and the electron-poor 

tetrazine units, with anion-tetrazine contacts ca. 0.4 Å shorter than the sum of their van der Waals 

radii (3.17 Å). 



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Figure 2 | Exploiting electrostatics for guest binding. a, The charge of the assembly dictates the binding strength of 

guests inside 7 and 8 (Sallé60,67). b, Anion-π interactions lead to the formation of different architectures, depending on 

whether one BF4
– or two SbF6

– anions are bound (Chifodes & Dunbar68). c,d Multiple anions are bound in close 

proximity within 11 (Lusby69), whereas surfactant molecules bind in 12 anticooperatively (Hardie & Fisher70). e, 

Polarised functional groups are oriented towards the metal corners of cages, as in cube 13 (see cutaway, at right) 

(Ward71). 

 

Lusby and co-workers reported multiple anions to be bound within 11 by electrostatic 

complementarity between the cationic host and anionic guests, along with favourable CH∙∙∙X 

hydrogen bonds, which were hypothesised to overcome electrostatic repulsions between guests 

(Figure 2c).69 The encapsulation of two detergent molecules within 12 was described by Hardie, 

Fisher and co-workers. Favourable van der Waals interactions between the alkyl chains of the guest 

and the aromatic surfaces of the host, along with electrostatic interactions between host and guest, 

led to the binding of two sulfonate guests within the host, with negative cooperativity (Figure 2d).70 

Cube 13 contains electron-poor pockets next to its metal centres (Figure 2e).71 Electron-rich 

guest moities orient within these pockets towards the positively-charged metal centres, with their 

binding reinforced by CH∙∙∙O hydrogen bonds of less than 3 Å. Two equivalents of dimethyl 



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methylphosphonate are bound at opposite poles of the interior of the cage, thus maximising contact 

with regions of high local positive charge.  

 

2.4 Maximising host binding surface 

If a host is capable of adopting multiple conformations, the restriction imposed on the scaffold 

upon guest binding reduces the number of degrees of freedom of the host framework, decreasing 

any favourable entropy change associated with guest binding. Rigid components are thus often 

favoured in the construction of cages, so as to maximise guest binding affinity.  

Closing off the faces of polyhedral cages with rigid or sterically-demanding ligands can help to 

favour internal guest binding.28 This practice takes advantage of the enthalpically favourable non-

covalent interactions generated between host and guest molecules upon encapsulation. Large arenes 

– porphyrins and polyclic aromatic hydrocarbons – have thus been used with great success as cage 

panels. The advantages of employing these moieties are twofold: 1) they are structurally rigid, 

lessening unfavourable entropy changes associated with locking of host conformations upon guest 

encapsulation; and 2) they offer substantial, polarisable surface area for van der Waals or π∙∙∙X 

interactions with guests.  

A comparative study of the guest binding properties of edge-panelled tetrahedra (hosts 14–21; 

Figure 3a) underscores the importance of maximising the degree of cavity enclosure in promoting 

guest encapsulation.72 Tetrahedra with open faces were less adept at binding small molecule 

payloads than those with closed-off faces. This was echoed in a comparison of the guest-recognition 

properties of  cubes 22 and 23 (Figure 3c), wherein only closed-off 23 bound guests.73 

Other capsules tiled with anthracene panels have been shown to bind electron-deficient guests, 

planar and spherical aromatic compounds, as well as structurally more complex and asymmetric 

guests like dyes, fluorophores and oligo(lactic acid)s.74-77 Guest binding in these instances is often 

aided by the hydrophobic effect in water, and reinforced by the large π-surface surrounding the 

encapsulated guest. Stabilising CH∙∙∙π interactions, which are amplified in water, are also established 

between host and guest upon binding.78 Cage 24 is capable of encapsulating two S6 or two S8 

molecules (Figure 3b); the guests in the former instance dimerise under UV light to form an S12 

cluster.79 Loose contacts between this host and its guests suggest that guest binding is also reinforced 

by S∙∙∙π interactions, in addition to the hydrophobic effect.  



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Figure 3 | Minimising empty aperture space can maximise host-guest contact, promoting central binding. a, The 

larger the enclosing surface the greater the diversity of host-guest chemistry in a series of tetrahedral cages (Nitschke72). 

b, A water-soluble lantern-shaped host with anthracene panels can selectively encapsulate either S6 or S8 molecules 

(Yoshizawa79). c, Adding anthracene moieties to a face-capping ligand can enable host-guest chemistry, even when the 

central void becomes larger (Nitschke73). 

 

2.5 Unsaturated metal sites 

Incorporation of coordinatively-unsaturated metal sites in metal-organic cages offers an 

opportunity to direct the binding and orientation of internal guests, as well as the potential to shape 

guest reactivity. Such coordination sites may be built into a ligand, enabling binding processes to 

occur inside the faces of a cage. When a single guest binds across multiple metal sites, binding is 

aided by the chelate effect, potentially leading to very high association constants (Ka > 1020 M–1). 

Sanders, Anderson and others have used this approach to template the formation of 

metallomacrocycles containing metalloporphyrin units.80-82 Employing metalloporphyrins that can 

bind one or more axial ligands enables the generation of diverse macrocycle sizes and morphologies: 

a fourfold-symmetric porphyrin template generated 4-mer macrocycle 25 (Figure 4a);83 12-mer 

‘caterpillar-track’ 26 was synthesised using two sixfold-symmetric templates (Figure 4b).84 Similar 



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metal-directed guest-binding involving metalloporphyrins has been employed by de Bruin and co-

workers to bind guests capable of size-selective catalysis.85,86 Conversely, cages with unsaturated 

coordination sites can bind additional metal ions following cage formation.87 

Coordinatively unsaturated metal sites at the corners of cages can also promote the binding of 

guests that are capable of binding as ligands. Such metal ions include CoII and CuII, with singly-

occupied d-orbitals, or square planar PdII, with a fully occupied 𝑑𝑧2 orbital that can facilitate the 

directional binding of guests at axial positions. Metal-guest interactions were initially described by 

Amouri and co-workers in a series of dimetallic structures templated by BF4
–.88-90 Direct MII···F 

interactions between the guest and the unsaturated metal centres of the host could be identified in 

complexes 27 and 28, the latter of which also bound BF4
– at its external metal faces (Figures 4c&d). 

Hooley and co-workers observed a similar interaction between PdII
2L4 cage 29 and an internally-

bound p-dicyanobenzene guest (Figure 4g).91 The association constant scaled with the solvent 

employed: more polar solvents out-competed the guest. 

Direct coordination to unsaturated metal sites can be used to promote through-bond electronic 

communication between the host and guest, regulating subsequent binding events. Aida, Tashiro 

and co-workers reported the preparation of cyclic architecture 30, constructed from a set of cofacial 

diporphyrin units enclosing a central cavity.92 The arrangement of these metal sites promoted 

positive heterotropic cooperativity: the co-encapsulation of one 4,4'-bipyridine molecule with one 

molecule of C60 was favoured over the binding of homotropic guest configurations, which displayed 

anticooperative binding (Figure 4e).  

Specific guest lengths and geometries can also bring about conformational changes in the host 

as a consequence of coordination to metal sites. Metallomacrocycle 31 twists and dimerises upon 

binding aliphatic dicarboxylates.93 Multipoint coordinative binding enforces a saddle-shaped 

conformation of the dimer, with either two or four guests bridging its cavity to stabilise the deformed 

structure (Figure 4f).  



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Figure 4 | Metal binding sites installed on the centres of ligands, or at the corners of assembles, can be used to 

drive the binding of polydentate guests. a and b, Top and side views of two macrocycles templated by either one tetra- 

or two hexa-dentate polypyridyl units (25: Sanders83; 26: Anderson84). c and d, BF4
– coordinates to both internal and 

external transition metal sites of cages (Amouri88,90). e, Different modes of cooperativity between guests were observed 

within 30, during the formation of homo- or hetero-tropic guest pairs, where the coordination of one guest promotes a 

favourable environment for the binding of a second, different guest (Aida & Tashiro92). f, Coordinatively-unsaturated 

ZnII sites can be used to form dimeric macrocycle 31 upon binding aliphatic dicarboxylates (Nabeshima93). g, Dipole-

cation interactions can stabilise specific guest orientations (Hooley91). 

 

2.6 Intermolecular interactions between guests 

Initial studies into generating heterotropic guest configurations within hosts relied upon the 

hypothesis that a cavity too small for an AA homotropic guest pair, but too large for a BB homotropic 

guest pair, might trap the AB heterotropic guest pair selectively.92 Engineering such heterotropic 

guest binding thus relies on multiple guests being stabilised inside the host by non-covalent forces, 

such as hydrogen bonding and van der Waals interactions. The groups of Rebek94-96 and Fujita50,97 

have both used this method to stabilise heterotropic guest configurations in organic and metal-

organic hosts, respectively. In heteroleptic host 32, Fujita and co-workers reported the encapsulation 

of nucleobase pairs, held together by hydrogen bonds, in an aqueous environment (Figure 5a).98 The 



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hydrogen bonds between two nucleotides are usually too weak to hold the base pair together in 

water. They are stabilised by encapsulation within the host, where water is not present to compete 

with base pairing. The selective formation of anti-Hoogsteen-type base pairs is observed instead 

(Figure 5a.i). Subsequent studies showed that the formation of single Watson-Crick GC base pairs 

was preferred over mismatched base pairs with weaker hydrogen-bonding motifs.99 

Intermolecular donor-acceptor interactions between guests have likewise been observed upon 

binding in supramolecular hosts. Such cases involve heterotropic guest combinations, requiring two 

guests with different electron densities capable of binding in close proximity. Yoshizawa and co-

workers demonstrated this concept in the co-encapsulation of polycyclic aromatics with boron-

dipyrromethene (BODIPY) dyes in 24 (Figures 5c,d).100 The electronic properties of the aromatic 

co-guest employed were observed to tune the fluorescence wavelength of the system upon 

co-encapsulation, with emission ranging from green to orange. 

 Cyclopentadienyl iridium- and rhodium-containing metal complexes are only encapsulated 

within 1 in the presence of a co-encapsulating aromatic guest (Figure 5b).101 The UV-Vis 

charge-transfer bands of these host-guest complexes were observed to shift with the oxidation 

potential of the encapsulated electron-poor unit. These studies reinforce conclusions drawn from 

analogous organic host-guest systems,102 which suggest that orbital overlap and electron 

delocalisation between guests are driving forces in the formation of hetero- rather than homo-tropic 

guest adducts.  

Heterotropic guest configurations resembling Magnus’ salt have been prepared by Shionoya 

and co-workers within PtII
2L4 host 33 (Figure 5e).103 This complex was able to bind positively-

charged species within a positively-charged host by encircling the central cationic guest with two 

anionic guests. The resulting pentanuclear stack of PtII cations is stabilised by Coulombic attraction 

both within the host, and between host and guest. 



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Figure 5 | Intermolecular interactions between guest species, as well as between host and guest, stabilise 

heterotropic guest configurations. a, The formation of an anti-Hoogsteen-type base pair is promoted in an aqueous 

environment within 32 (Fujita98). b and c, Electron-deficient guests pair with electron-rich guests within capsules (b, 

Reek101; c, Yoshizawa100), d, tuning the optical properties of the assemblies (Yoshizawa100). e, Favourable interactions 

between metal complexes of opposite charges can stabilise stacks of metal ions within host 33 (Shionoya103). 

 

 

3. Segregation of space 

Two guests can bind in two separate spaces concurrently within a host. Engineering such cavity 

division in synthetic systems is not easy: traditional self-assembly protocols tend to generate 

architectures with distinct faces or edges; the cavity is generated as a consequence of this process, 

usually as a single, continuous volume. Bridging such a cavity typically involves either installing 

more than two parallel coordination sites on linear ligands, or generating interdigitated architectures. 

These two methods are discussed in turn below. 

 

3.1 Multi-topic axial struts 

Ligands containing more than two sites with parallel coordination vectors can coordinate metals 

at both their terminal and central positions simultaneously.104 Lehn and co-workers introduced this 

concept by generating cylindrical heteroleptic structures such as 34, where linear oligo(bipyridine) 

ligands act as axial supports for the perpendicular coordination of up to four parallel 

hexaazatriphenylene linkers (Figure 6a).105 The three separate cavities within this assembly were 

capable of binding small anions. The number of cavities in the resulting architecture was a 



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consequence of the number of available coordination sites on the axial ligand, and the number of 

guests encapsulated could thus be tuned by altering the height of the cylinder.  

This concept has been further developed by the groups of Bosnich106,107 and Crowley108 to co-

encapsulate different molecular guests in distinct cavities. The technique relies on tailoring segments 

between each coordinating moiety within the ligand, so that multiple cavities have different 

interior-facing functional groups. For instance, molecular rectangle 35, held together by 

4,4'-bipyridine struts, contains two binding sites for small platinum complexes (Figure 6c).106,107 

These guests bind with positive allosteric cooperativity, where K1 = (1.5 ± 0.2) × 103 M–1 and K2 = 

(5.2 ± 0.4) × 103 M–1.  

The same authors (supported by studies from the Hooley and Lusby groups) have observed that 

specific aromatic pillars directed the binding of specific guests: cavities surrounded by pyridyl rings 

bind cisplatin,108 whereas those surrounded by phenylene rings preferentially bind triflate anions64,91 

instead. In cage 36, this scaffold-dependent guest binding was used to design selective co-

encapsulation of the two guests.109 The ligands of 36 contain both pyridyl and phenylene moieties 

(oriented perpendicular to the length of the cage): triflate is hence encapsulated selectively in the 

middle cavity, while cisplatin binds in the surrounding cavities (Figure 6d). In this instance, placing 

N-donors unable to coordinate to metal ions throughout the ligand backbone allows the formation 

of distinct cavities, each with different electronic properties. 

Yoshizawa and co-workers extended this methodology to bind different guests in different 

stoichiometries in different cavities.110 While ‘molecular peanut’ 37 is able to accommodate two 

fullerenes in separated cavities, a unique 1:1:2 host:guest:guest' complex results when diamantane 

and phenanthrene are introduced simultaneously (Figure 6e). Molecular modelling studies suggested 

that this binding configuration is promoted by changes in the volume of the second cavity upon 

binding a molecule in the first: binding of diamantane in Cavity 1 increases the volume of Cavity 2 

by 6%, whereas binding two molecules of phenanthrene in Cavity 2 decreases the volume of Cavity 

1 by 4%. In both cases, the complementary guest is thus favoured over homotropic guest pairing.  

Jeong and co-workers synthesised a folded metallocycle 38 capable of binding two guests in 

symmetrical cavities (Figure 6b).111 The bent geometry of 38 directs its hydrogen-bond donors into 

separated cavities, enabling small molecules with hydrogen-bond accepting units to bind within 

these. Minimal changes in cooperativity are observed upon changing the length of alkynyl chains at 

the central ligand crossing. The segregation of donating units drives association irrespective of the 

cavity size. 



15 

 

 

Figure 6 | Dividing the space within a supramolecular capsule generates distinct binding pockets. Cavity divisions 

can be achieved by: a, adding spacer units (Lehn105); b, isolating moieties that can participate in intermolecular 

interactions with guests (Jeong111); c, employing ligands that physically separate binding regions (Bosnich107); or d and 

e, appending secondary coordination sites to ligands (36: Crowley;109 37: Yoshizawa110).  

 

3.2 Interlocked cages 

Interlocked cage architectures, by geometrical necessity, generate at least three separate cavities: 

two distinct voids located in the interlocking cages, and one generated by the space between them.  

Fujita and co-workers have explored the spaces within interlocked heteroleptic cages that were 

generated from combinations of two- and three-fold symmetric ligands. The first example of this 



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structure type was composed of two interlocked heteroleptic M3LL' cages; however, the favourable 

aromatic stacking between ligands resulted in a compact assembly containing no void spaces.112 The 

extrapolation of this approach by using axial ligands of different lengths enabled multiple pyrene 

molecules to template and bind within the three different cavities of hosts 39 and 40 (Figures 

7a,b).113 Importantly, the two peripheral cavities generated by this process were only observed to 

bind single molecules: altering the ligand length changed only the number of molecules that could 

be bound in the middle cavity.  

 A series of catenated cages based on PdII
2L4 structure-types with banana-shaped ligands have 

been generated by Clever and co-workers (Figures 7c,d).114,115 Depending on the ligand bend angle 

and the substituents at the centre of the ligands, hosts akin to 41 and 42 can bind two or three guests 

in different cavities. Subtle changes in the ligand or template can lead to significant changes in the 

cavity size of the central, as compared to the peripheral, guest binding sites. Allosteric regulation of 

anion binding is often observed as a result, as discussed in section 3.3. 

Multi-cavity architectures solve a problem associated with large hollow assemblies, wherein 

large void volumes prevent site-specific interactions between guests.104 They also enable the number 

and shape of cavities to be tuned, by simply changing the number of coordination sites within an 

axial ligand and the spacing between these sites. They are most readily expressed in the form of 

specific geometries, cylindrical architectures in particular. Other interlocked cage topologies have 

been reported, but the extensive overlap of ligands within these structures renders them unsuitable 

for guest binding.116  

Likewise, larger multi-compartment cages, where an external shell encloses an inner structure, 

have been generated.117,118 These structures contain multiple distinct cavity geometries, which 

Schmidt and co-workers reported could bind more than thirty equivalents of 7-amino-4-

methylcoumarin.119 

 



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Figure 7 | Catenated architectures generate multiple cavities (a-e); two guests cause reconstitution of cavities to 

express unique structures (f-h). a and b, Interlocked cages 39 and 40 bind pyrene molecules (Fujita113). The length of 

the linear bipyridine ligand dictates the number of guests bound in the central cavity; the terminal cavities are only 

observed to bind one pyrene molecule each. c and d, Depending on the size and shape of the ligand, 41 and 42 can bind 

up to three different guests in their three cavities (Clever114,115). e, Exchange of two BF4
− anions in the peripheral cavities 

of 42 leads to expansion of the central cavity, which can then bind different neutral guests (figure adapted from 

Clever120). f, Void-less structure 43 transforms into cage 44 upon recognition of two coronene guests (Severin121). g, 

Sandwich complex 45 exploits positive allosteric cooperativity when binding two croconate guests (Nitschke122). h, 

Two fullerenes bind with all-or-nothing positive allosteric cooperativity to cuboctahedral assembly 47 and cause its 

reconstitution to give 48, an S6-symmetric diastereomer (right: top and side views of the metal connectivities of 47 and 

48) (Nitschke123). 

 



18 

 

4. Structural adaptation 

Allostery in biology relies on small configurational changes altering the size or shape of binding 

pockets: one binding event causes a structural change in the receptor, leading to an improvement or 

weakening of secondary binding events at distant sites. Supramolecular mimics of such receptors 

that can adapt their morphology or cavity size in response to an initial guest-binding event may thus 

be able to tailor the space available for a second guest. Cage 37 (Figure 6d) realised this concept by 

the compression and expansion of individual cavities, whereas the catenated cages of Clever and co-

workers114 slip past each other to regulate cavity size upon guest binding.120 Synthesised with three 

BF4
– anions occupying its pockets, 42 can alter the sizes of its cavities upon the introduction of two 

Br– or Cl– guests. The top and bottom cavities contract to accommodate the smaller halides, while 

the central cavity, still holding a BF4
– anion, enlarges (Figure 7e).115 The resulting expansion of the 

central cavity weakens the affinity for BF4
–, enabling neutral guests, such as benzene or 

cyclohexane, to replace BF4
–.  

Severin and co-workers have also reported a capsule that can bind two guests concurrently. 

Assembly 43 expands upon recognising two coronene or two perylene molecules, opening up a 

guest-binding cavity to generate new architecture 44, with a cavity of ca. 500 Å3 (Figure 7f).121 In 

43, the carboxylic acid functionalities on the naphthalene ligands are arranged horizontally, whereas 

they switch to a vertical orientation upon guest recognition in 44. This mechanism for cavity 

expansion takes advantage of flexible connections between the metal centres and the ligand, 

reminiscent of the ‘induced fit’ mechanism observed in some biological receptors. Similarly, 

coordinatively unsaturated CdII sites in CdII
4L2 receptor 45 enable the cooperative loading and 

release of croconate guests (Figure 7g).122 The binding of one guest molecule between two 

unsaturated CdII sites leads to the formation of configuration 46, which is better able to bind a second 

croconate, leading to positive cooperativity. 

Two fullerenes cause a reconstitution of cuboctahedral assembly 47 to express 48, an 

S6-symmetric diastereomer of the original O-symmetric structure (Figure 7h).123 Two fullerene 

guests template the formation of 48, suggesting all-or-nothing cooperative binding of these guest 

within the cavity. In the O-symmetric state, 47 displays negative allosteric cooperativity in binding 

anionic guests; following transformation to 48, positive cooperative binding of icosahedral 

carborates is observed. The transformation between distinct diastereomers thus regulates the 

cooperative binding capabilities of the host. 

 



19 

 

5. External/peripheral interactions 

While the central cavities of coordination cages have attracted significant interest, their 

peripheral environments can also be used in guest recognition processes. For instance, two binding 

sites at the periphery of cubic capsule 49 regulate the internal binding of anions (Figure 8a).124,125 

This method relies on the presence of different binding environments around the periphery of the 

capsule, adapted to different guests: neutral phosphines were observed to associate with the cube 

face; anionic BPh4
– associated with a cleft between adjacent faces; and Mo2O7

2– bound inside. 

Binding at either of the peripheral locations of 49 decreased the affinity for the subsequent internal 

binding of an Mo2O7
2− anion, providing two distinct modes of allosteric inhibition.   

Similar allosteric effects were observed in tetrahedral FeII
4L6 cage 50, adorned with trivalent 

crown-ether receptors (Figure 8d).126 The binding of four trivalent cations to the peripheral crown-

ether units restricted the flexibility of the cage framework, thereby limiting the expansion of the 

cage’s apertures. When the tripodal receptor sites are empty, the exchange rate of PF6
– for ReO4

– 

within the cavity is rapid. Anion exchange is slowed upon the binding of triprotonated 

tris(aminoethyl)amine at the cage’s periphery. 

Raymond, Bergman and co-workers explored the concept of external guest binding more 

generally in water-soluble host 2, detailing that the exterior binding of guests was enthalpically-

driven, whereas internal encapsulation was driven by entropy (Figure 1b),44 conclusions reinforced 

by a subsequent study.127 Similarly, the concentration of externally-bound guests affects the rate of 

guest exchange within the central cavity: increasing the concentration of external binders is inferred 

to decrease host flexibility, decreasing the rate of guest exchange.128,129 

 The allosteric effect of binding guests in both internal and peripheral binding sites has been 

investigated in MII
6L4 pseudo-octahedron 51 (Figure 8b).130 As with Fujita’s original PdII

6L4 host,131 

alternate faces of this cage are panelled with ligands and open apertures, providing both a closed-

off central void and distinct peripheral binding sites, respectively. Both internal and peripheral 

guests can be bound simultaneously by 51, with no loss of binding affinity for either guest. Cages 

with the framework of 51 can also be templated by peripherally-binding anions,132 enabling the 

generation of hosts capable of binding other guests centrally. Studies on anion-cornered 

architectures have echoed these findings.133 

Vacant coordination sites at the periphery of a cage can also be used to bind multiple guests. For 

example, in octahedron 52 reported by Shionoya and co-workers, triflate anions coordinated to the 

internal sites exchanged for p-toluenesulfonate anions, while the exterior-facing triflate anions 

remained (Figure 8c).134 



20 

 

 

Figure 8 | Internal and peripheral binding sites together regulate guest binding. a, System of allosteric regulation 

modulating internal guest binding through two distinct exterior sites of 49 (figure adapted from Nitschke125). b, Binding 

suitably-sized triammmonium ions to crown-ether-decorated host 50 modulates the rate of exchange of a centrally-

bound anion (Nitschke126). c, Two distinct guest-binding locations in 51 enable mutually-independent binding events to 

occur simultaneously (Nitschke130). d, External triflate anions are not displaced from the Hg2+ sites of 52, whereas 

interior triflates are substituted by tosylate ligands (Shionoya134). 

 

6. Applications of multiple guest binding beyond allostery  

The installation of multiple binding sites can imbue coordination cages with the ability to carry 

out catalytic transformations and structural reconfigurations, extending beyond traditional concepts 

of allostery. 

 

6.1 Architectural templation 

Non-central binding configurations are observed within a series of mer-cornered Dn-symmetric 

architectures based on C2 symmetric ligands.135,136 In all cases, anions located in the peripheral 

pockets of architectures 53–55 are necessary for their generation (Figure 9a). These anions 

collectively template the formation of these structures, with anion displacement leading to 

structural rearrangement. In the case of the largest structure of this series (55), six PF6
– anions serve 

as peripheral templates, in pockets in the walls of the structure, with a seventh (Tf2N
–) observed in 

the central cavity. The size of the peripheral cavities in the framework of 55 scales with the ionic 



21 

 

radius of the metal ion employed, allowing different metal cations and anions to be used in the 

construction of architectures of this type.135 A version of structure 54 having lipophilic alkyl tails 

on its aniline residues will insert into lipid bilayers, serving to gate the flow of ions through the 

membrane. Dodecylsulfate anions are too large to pass through the central channels of this 

structure, instead binding and blocking the flow of ions though the channel, gating the current 

flow.137 

In similar fashion, Lützen and co-workers demonstrated that two BF4
– templates, sitting in 

opposite corners, stabilise twisted architecture 56, based on 1,1'-bi-2-naphthol (BINOL) linkages 

(Figure 9b).138 Fujita and co-workers also demonstrated the templation of tubular structure 57 

(Figure 9c) using two aromatic, anionic biphenylcarboxylate guests.139 The guests in this cage cap 

the ends of the tube, rather than binding centrally. In both 56 and 57, a void is formed in the centre 

of the structures. No guests are observed to occupy these cavities in solution, suggesting the 

possibility of subsequent guest encapsulation. 

 

6.2 New modes of synthetic chemistry and catalysis 

The ability to confine two or more molecules in proximity can facilitate reactions between co-

encapsulated guest molecules within synthetic cavities.140,141 Diels-Alder cyclisation reactions 

inside self-assembled architectures feature prominently in the development of reactions between 

guests. The first example of this strategy was reported by Rebek and co-workers using an organic 

host;95 a similar procedure was developed by Fujita’s group to synthesise cyclised products using 

either thermal or light energy (Figure 9d).140 The transition states of these reactions are stabilised 

through confinement, leading to reaction acceleration or to the observation of products that cannot 

be formed in the absence of the cage. Cyclisations,142 photodimerisations,143,144 asymmetric 

photoadditions,145 photochemical oxidations,146 trimerisations147 and site-specific organometallic 

photodissociations148 have all been reported within 1. 

The co-encapsulation of guests is central to the success of several catalytic processes reported 

by Raymond, Bergman, Toste and co-workers within host 2.149-152 The initial substrate is bound in 

the presence of small molecules, leading to accelerated Nazarov cyclisations in the presence of 

H2O,153 aza-Cope rearrangements with a co-encapsulated proton source154 and an SN2 reaction with 

CD3OD that maintains the absolute stereochemistry of the substrate.155 The binding of two guests 

in these instances is transient: the binding and subsequent reaction of two molecules brings about 

displacement of the final product from the cage cavity.  



22 

 

Reek and co-workers have demonstrated similar transient co-encapsulations in Pd12L24 

spheres,156-158 where initially-bound substrates react with moieties embedded internally on the 

walls of these structures. Fujita and co-workers have shown that such catalysts can participate in 

cascade reactions.159 These nanospheres can also guide the growth of SiO2 internally, generating 

monodisperse silica nanoparticles.160 

Cage 3, reported by Mukherjee and co-workers, binds two aldehyde-substituted aromatic 

guests, and accelerates the condensation of these aldehydes with Meldrum’s acid in situ (Figure 

9f).52 The Knoevenagel condensation that occurs within 3 is promoted by the hydrophobic 

environment of the cage; water is eliminated from the central hydrophobic pocket, driving the 

reaction forwards. Fujita and co-workers reported a similar condensation reaction within 1.161 

 



23 

 

 

Figure 9 | Structures emerging from the interaction of multiple guests with coordination cages. a-c, Architectures 

templated by two or more guests (a, Nitschke;135 b, Lützen;138 c, Fujita139) d-f, New synthetic pathways (d, figure 

adapted from Fujita;140 e, Ward;162 f, Mukherjee52). g and h, Structural transformations that result from adding multiple 

guests, leading to the capture and release of guests in g (g, Kuroda;163 h, Chi164). 

 



24 

 

More recent studies have approached catalytic transformations from an electrostatic 

perspective, employing the peripheral windows of structures and their positive charge to enforce 

the association of basic anions at peripheral binding sites. These anions then promote catalytic 

transformations of bound guests. Cage 13 catalyses Kemp elimination by increasing the local 

concentration of OH– around its apertures (Figure 9e).162 Turnover within the system is driven by 

the negative charge of the guest following its transformation; whereas the starting material is 

hydrophobic and binds with high affinity to 13, the product of the reaction becomes hydrophilic 

and is thus ejected from the cage to complete the catalytic cycle. This process is autocatalytic165 – 

the eliminated anionic guest was observed to associate to the apertures of 13, deprotonating the 

bound substrate and progressively accelerating the reaction. This work builds upon a similar 

catalytic process described by Raymond, Bergman and co-workers, where the stabilisation of 

cationic intermediates within the negatively-charged shell of 2 promotes processes that are 

ordinarily acid catalysed, even under basic conditions.166 

 

6.3 Structural rearrangements and guest release 

The conversion of one structure to another is often driven by the binding of a guest to the 

product.167,168 However, this process is rarely concerted, involving more than one templating unit. 

Kuroda and co-workers reported the ability of two naphthalenesulfonate anions to induce the 

transformation of mechanically interlocked cage complex 58 to its monomeric form 59 (Figure 9g). 

This process reversed following the addition of NO3
–, which occupies three separate pockets of the 

catenane, thus demonstrating a system of reversible host-guest uptake and release coupled to 

structural transformation.163,169 Interconversion between macrocycles of different sizes was also 

reported by Sun and co-workers: different anions template cyclic structures from 4 to 9 repeat units 

in size.170 Two or more anions were often necessary to drive these conversions, with models 

suggesting an induced fit mechanism in the generation of specific macrocycle sizes.  

Conversion between interlocked and unthreaded structures was also demonstrated by Chi and 

co-workers using two electron-rich moieties.164 Without guests, two cages interpenetrate to 

generate catenane 60, but the addition of pyrene leads to formation of cage 61, housing two guest 

molecules, with both edge-to-face and face-to-face aromatic interactions between the host and 

guest driving encapsulation (Figure 9h). Such studies build upon examples of the templation of a 

specific structure by a single guest.171-173 Transformations employing more than one guest may lead 

to products with greater structural complexity, as multiple guests generate multiple cavities. 

 



25 

 

6.4 Biomedical integration 

Metal-organic cages have found use in two biomedical areas: imaging and drug delivery.174,175 

In both cases, functions may derive from the host alone.176 In the case of drug delivery, however, 

the ability to bind multiple guests within a synthetic cavity increases the amount of material that can 

be loaded and delivered.177 For instance, the cytotoxicity of assemblies encapsulating two molecules 

of cisplatin was observed to be significantly larger than cisplatin alone.178,179 The cages themselves 

displayed low or no cytotoxicity, while the host-guest complexes were cytotoxic to human lung 

cancer cells, marking these assemblies as promising drug delivery vehicles. 

Lippard and co-workers exploited the amphiphilic nature of platinum(IV) prodrugs to selectively 

encapsulate four such guests within an analogue of 1.180 This arrangement relied on hydrophobic 

adamantyl functionalities binding internally, whereas hydrophilic carboxylate moieties were 

preferentially exposed to the surrounding water. Importantly, the high positive charge of the 

assembly facilitated cellular uptake. The payload was released upon reaction with biological 

reductants, increasing the local concentration of prodrugs within the cell, leading to apoptosis with 

cytotoxicity comparable to that of cisplatin.  

 

7. Conclusions and perspective 

Established strategies for improving guest binding rely upon minimising panel gaps within a 

structure and fitting the size and shape of a guest within the cavity of the host.28 However, these 

rules limit the diversity of guest binding behaviour that may be observed. Peripheral interactions 

between host and guest can be enabled and enhanced by wide gaps between ligands, and catalytic 

turnover often relies on apertures being large enough for a transformed guest to be ejected. The only 

definitive method for improving the internal binding of guests is to make coordination cages stable 

and soluble in water. To promote multiple, peripheral, and more diverse host-guest interactions, 

multiple guest-specific binding regions must be engineered to coexist within a single host. While 

each of the strategies detailed in this Review have been examined in isolation, successfully binding 

multiple guests often relies on synergic combinations of these methods, which complement each 

other to bring about complex binding interactions and phenomena.  

Metal-organic self-assembly often produces unpredicted outcomes, which can then be translated 

into sets of new synthetic rules.23 The resulting structural diversity of coordination cages has 

translated into wide-ranging functions associated with encapsulation: guest binding, reaction, 

catalysis, and delivery. Although organic hosts may bind guests with higher affinities than 



26 

 

metal-organic cages, many of the principles governing encapsulation are equally valid across all 

classes of host. A key advantage of using coordination cages is that structural (and thus functional) 

diversity can be achieved in few steps from simple ingredients, enabling a wide range of guest-

binding conditions to be tested and mapped, and thus new methods for engineering multiple guest 

binding events to be uncovered and subsequently widely employed. 

Taking inspiration from biological allostery, chemists have tuned the properties of coordination 

cages to express functions that extend beyond the natural processes of binding regulation. Such 

structures may serve as the building blocks of new chemical systems that are capable of weighing 

multiple input signals – different chemical species, heat, or light, for example – to generate distinct 

output events, such as guest uptake and release. In a manner akin to signal transduction, the output 

of one system component may itself be an input for another part of the system. These chemical 

networks may ultimately be capable of complex information-processing and computation tasks, 

similar to those undertaken by living systems. 

 

  



27 

 

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