1 Introduction

Supramolecular chemistry emphasizes on applying noncovalent interactions to synthesize materials at various scales [1,2,3,4]. On account of dynamic nature of noncovalent interactions, resultant aggregates are responsive to diverse kinds of external stimuli such as light, pH, heat, ultrasound, redox agents, and enzyme action [5,6,7]. Stimulus responsive property allows the fabrication of smart materials that show promising applications in the areas of cargo delivery, drug release, actuators, soft robotics, and so on [8,9,10,11]. Noncovalent interactions could be introduced into building blocks via delicate design [12,13,14,15,16,17,18]. Among these interactions, host-guest interaction is a powerful mean to fabricate complex building blocks for further self-organizing into different micro-/nanoarchitectures. Host-guest interaction occurs typically between macrocyclic molecules and suitable guest molecules. The discovery of macrocyclic hosts such as crown ethers, cryptands, cyclodextrins, calixarenes, cucurbiturils, pillararenes, and many others has significantly extended the application scope of host-guest interaction.

Some host-guest inclusion complexes possess amphiphilic property, enabling their spontaneous self-assembly in specific environments. This kind of amphiphiles belongs to supramolecular amphiphile [19,20,21,22]. The architectures self-assembled from host-guest amphiphiles are greatly vulnerable to external stimuli as compared to that from traditional amphiphiles. Once the host-guest interaction is interfered, the dissociation of amphiphiles shall happen, resulting in the disintegration of entire architectures. This dynamic character endows a great flexibility for rational design of smart materials toward advanced applications. For instance, upon light irradiation, azobenzene/cyclodextrin inclusion complexes could undergo the dissociation, arousing the collapse of supramolecular hydrogels [23, 24].

Host-guest supramolecular amphiphiles have been used to fabricate various kinds of soft materials at all scales, including zero-dimensional micelles and vesicles, one-dimensional nanofibers/nanotubes, two-dimensional membranes, and three-dimensional gel networks [25,26,27]. Among them, vesicles have attracted considerable attention owing to their unique applications in drug delivery, biomimetics, biosensors, and so on [28,29,30]. Vesicles are a spherical closed system with bilayer membrane, which can be constructed by some amphiphilic molecules spontaneously in aqueous solution [31, 32]. Amphiphiles including phospholipids, polymers, and surfactants have been proven to be ideal building blocks to prepare vesicles [33, 34]. The formation of vesicles is more favorable when the volume of hydrophobic part (v), the length of hydrophobic part (l), and the volume of hydrophilic head (a) of amphiphiles have a specific ratio (0.5 < v/la < 1) according to the theory of molecular packing parameters [35]. As compared to other architectures, vesicles have a special topology, possessing flexible membranes with hydrophilic cavity capable of carrying hydrophilic cargos. Meanwhile, the bilayer structures having hydrophobic interior could include hydrophobic cargos. In addition, structural similarity between cell membranes and vesicles enables highly efficient cell internalization of some vesicles.

Toward advanced biomedical applications, vesicle systems self-assembled from host-guest supramolecular amphiphiles are a promising group, ascribed to their significant adaptiveness. One can flexibly manipulate the release of desired dyes, drugs, and genes into targeted cells by various stimuli. By the design and screening of host and guest molecules, light-, redox-, electric field-, pH-, enzyme-, and chemical-responsive vesicle delivery systems have been developed, exhibiting sufficient therapeutic efficacy.

In this chapter, we summarize and discuss recent significant developments regarding the design, synthesis, and applications of vesicle systems prepared from host-guest supramolecular amphiphiles. At first, we discuss the fabrication of vesicles according to the type of macrocyclic molecules. Then, the loading capacity and stimulus responsive property of selected vesicles toward biomedical applications are introduced. This chapter is expected to provide a research update in this rapidly developing field (Scheme 1).

Scheme 1
scheme 1

Schematic illustration of supramolecular vesicles based on host-guest recognition

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2 Supramolecular Vesicles Based on Host-Guest Recognition

Diverse macrocyclic host molecules including cyclodextrin, calixarene, cucurbituril, and pillararene have been developed. The notable character of these host molecules is that they all have a unique cavity, empowering them with the ability to capture guest molecules and form inclusion complexes. For different kinds of host molecules, their cavities have different sizes and properties, resulting in the selectivity toward different guest molecules. Host molecules can form supramolecular amphiphiles with some specific guest molecules through host-guest recognition. The host-guest supramolecular amphiphiles are similar to phospholipids with hydrophilic head and hydrophobic tail, which can self-assemble into supramolecular vesicles under mild conditions. Thus, cyclodextrin-guest supramolecular vesicles, calixarene-guest supramolecular vesicles, cucurbituril-guest supramolecular vesicles, and pillararene-guest supramolecular vesicles have been widely studied, as presented below.

2.1 Cyclodextrin-Guest Supramolecular Vesicles

According to literature record, cyclodextrins were discovered in 1891 [36]. But the development of cyclodextrin chemistry was slow, until the crystal structures of α-cyclodextrin and β-cyclodextrin were reported in 1942 [37]. Cyclodextrins are a family of cyclic oligosaccharides with a three-dimensional truncated cone structure [38]. The most common cyclodextrins are α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, with six, seven, and eight glucoses, respectively. The outside part of cyclodextrins is hydrophilic since there are a large number of hydroxyl groups on rims, while the inner cavity of cyclodextrins is hydrophobic. Hence, cyclodextrins have the ability to encapsulate hydrophobic guest molecules with suitable sizes within the cavity [39]. The encapsulation between cyclodextrins and hydrophobic species can lead to the formation of cyclodextrin-guest supramolecular amphiphiles. Cyclodextrin-guest supramolecular amphiphiles may then assemble into cyclodextrin-guest supramolecular vesicles spontaneously in aqueous medium.

α-Cyclodextrin and β-cyclodextrin have been used to construct cyclodextrin-guest supramolecular vesicles. Ji and coworkers synthesized a poly(ethylene oxide)-b-poly(2-methacryloyloxyethyl phosphorylcholine) diblock copolymer chain. Poly(ethylene oxide) moiety of this copolymer can be encapsulated by the cavity of α-cyclodextrin [40]. Then, the inclusion complex of α-cyclodextrin with the diblock copolymer could self-assemble into vesicles in phosphate-buffered saline solution (0.1 M, pH 7.4). More importantly, these vesicles were able to load and release hydrophilic doxorubicin (DOX) drug into cancer cells efficiently, showing potential pharmaceutical application in drug delivery.

Compared to α-cyclodextrin-guest supramolecular vesicles, β-cyclodextrin-guest supramolecular vesicles have gained more extensive attention [40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75]. Huang et al. reported a virus-like vesicle based on β-cyclodextrin-guest interaction [76]. The vesicle was constructed by β-cyclodextrin/[4-butyl-4′-(oxy-2,3-epoxypropyl)azobenzene] supramolecular amphiphile, which could be applied to deliver DOX owing to its good biocompatibility. Interestingly, hair-like structure was observed on the surface of the vesicle under UV light irradiation, of which morphology showed a great similarity to virus. Lots of β-cyclodextrin derivatives were synthesized to construct vesicles by Hao and coworkers. For example, they initially synthesized mono[6-deoxy-N-n-hexylamino-(N′-1-anthraquinone)]-β-cyclodextrin, and then native β-cyclodextrin was employed to recognize and encapsulate the obtained β-cyclodextrin derivative for transforming into vesicles [77]. This β-cyclodextrin-based supramolecular vesicle showed multiple responsiveness to pH and metal ions. In addition to native β-cyclodextrin, modified β-cyclodextrins can also be used as the host molecules to fabricate vesicles. Zhou and coworkers reported a hyperbranched supramolecular amphiphile, constructed by polyglycerol modified β-cyclodextrin (CD-g-HPG) as the host and long alkyl chain-containing adamantane derivative (AD-C18) as the guest (Fig. 1) [78]. This hyperbranched supramolecular amphiphile can assemble into vesicles in water. The vesicles were very sensitive for competitive host and would disassociate upon the addition of β-cyclodextrin.

Fig. 1
figure 1

Self-assembly and disassembly of supramolecular vesicles. (Reproduced with permission from [78]. Copyright 2012, American Chemical Society)

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2.2 Calixarene-Guest Supramolecular Vesicles

Calixarenes were firstly reported in 1944. The separation of calixarene mixture was challenging. Gutsche and coworkers made an excellent contribution for the calixarene development in 1981, and one-step large-scale synthesis of calixarenes was established [79]. More and more calixarene derivatives were synthesized from then on, attracting significant research attention on calixarene chemistry. The most common calixarenes are calix[4]arene, calix[6]arene, and calix[8]arene, with four, six, and eight phenol units, respectively. After suitable modifications, the solubility of calixarenes in aqueous solution could be increased dramatically, making them possible for supramolecular vesicle fabrication. Calix[4]arene derivatives are the commonly used calixarenes in the construction of supramolecular vesicles.

Compared to cyclodextrins, there were relatively fewer reports about calixarene-guest supramolecular vesicles [80, 81]. Liu and coworkers reported enzyme-responsive supramolecular vesicles based on calixarene inclusion complexes (Fig. 2) [82]. A calix[4]arene derivative, namely, p-sulfonatocalix[4]arene with good solubility in water, was synthesized. Natural myristoylcholine was employed as the guest to fabricate a supramolecular amphiphile with p-sulfonatocalix[4]arene. The p-sulfonatocalix[4]arene/myristoylcholine supramolecular amphiphile can further assemble into vesicles in aqueous medium. A hydrophilic model molecule, trisodium salt of 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS), was effectively loaded into the vesicular interior. Interestingly, the p-sulfonatocalix[4]arene/myristoylcholine supramolecular vesicles can release HPTS upon the addition of butyrylcholinesterase (BChE) within 4 h. Myristoylcholine was converted into myristic acid and choline catalyzed by BChE, causing the disassembly of the vesicles and release of HPTS. Excellent biocompatibility of p-sulfonatocalix[4]arene/myristoylcholine supramolecular vesicles was verified by cell experiments, implying that the vesicles were a suitable system for the drug delivery.

Fig. 2
figure 2

Schematic illustration of the construction of p-sulfonatocalix[4]arene/myristoylcholine supramolecular vesicles with cholinesterase responsiveness. (Reproduced with permission from [82]. Copyright 2012, American Chemical Society)

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2.3 Cucurbituril-Guest Supramolecular Vesicles

By the reaction of formaldehyde and glycoluril under acid condition, Behrend and coworkers synthesized cucurbiturils for the first time in 1905 [83]. Thanks to excellent work reported by Mock and coworkers in 1981 [84], the chemical structure of cucurbit[6]uril was revealed by NMR and X-ray crystallographic analysis, promoting further development of cucurbiturils. The most common cucurbiturils are cucurbit[5]uril, cucurbit[6]uril, cucurbit[7]uril, and cucurbit[8]uril, with five, six, seven, and eight glycoluril units, respectively. As pumpkin-shaped host molecules with lots of carbonyl groups on the ports of cavity, cucurbiturils show high affinity to cationic guests [85].

Among the family of cucurbiturils, cucurbit[8]uril is commonly used to fabricate supramolecular vesicles [86]. Kim and coworkers published the first cucurbit[8]uril-guest supramolecular vesicles in 2002 [87]. Cucurbit[8]uril can encapsulate 2,6-dihydroxynaphthalene and C12 or C16 alkyl chain modified viologen at the same time to form stable ternary inclusion complexes. The obtained cucurbit[8]uril-guest supramolecular amphiphiles can further assemble into vesicles in water. Such vesicles would collapse upon the addition of cerium(iv) ammonium nitrate, showing stimulus responsiveness to oxidants. As reported by Scherman and coworkers in 2014, pyreneimidazolium-labeled peptide and viologen-modified poly(N-isopropyl acrylamide) were simultaneously held in the cavity of cucurbit[8]uril to form an inclusion complex, and this ternary complex could self-assemble into cucurbit[8]uril-guest supramolecular vesicles when the temperature was above 35 °C (Fig. 3) [88]. Interestingly, such vesicles could deliver basic fibroblast growth factor effectively without the need of any stabilizing agents. The remained immunoreactivity of basic fibroblast growth factor in vesicles was at least three times higher (after 5 days) than that of basic fibroblast growth factor itself. In addition, basic fibroblast growth factor encapsulated in the vesicles could stimulate the growth of fibroblast cells rapidly by a 3T3 cell proliferation assay, indicating its potential application as an injectable carrier in tissue repair.

Fig. 3
figure 3

Schematic representation of the formation of cucurbit[8]uril-guest vesicle with temperature responsiveness. (Reproduced with permission from [88]. Copyright 2014, the Royal Society of Chemistry)

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2.4 Pillararene-Guest Supramolecular Vesicles

Pillararenes are one of the youngest generations of macrocyclic molecules. Pillararenes were first synthesized by Ogoshi and coworkers via the condensation reaction of paraformaldehyde and 1,4-dimethoxybenzene in 2008 [89]. Pillararenes have become a new engine of host-guest chemistry, promoting vigorous development of supramolecular host-guest vesicles. The most common pillararenes are pillar[5]arene, pillar[6]arene, and pillar[7]arene, with five, six, and seven hydroquinone units, respectively. Easy functionalization, good solubility in solvents, and symmetrical rigid electron-rich structures make pillararenes excellent host molecules to encapsulate various electron-deficient guests [90, 91].

Modified pillar[5]arene, pillar[6]arene, and pillar[7]arene could all be employed to construct pillararene-guest supramolecular vesicles [20, 92,93,94,95,96,97,98,99,100,101,102]. For instance, Wang and coworkers reported pillar[5]arene-guest supramolecular vesicles recently [103]. A water-soluble pillar[5]arene (WP5) as the host and a diphenylboronic acid derivative as the guest were used to fabricate pillararene-guest supramolecular vesicles. Insulin and glucose oxidase could be encapsulated into the interior of the vesicles effectively. The disassembly of the insulin delivery vesicles could be realized under hyperglycemic, low pH, or high H2O2 concentration conditions, triggering the release of insulin. Furthermore, smart insulin delivery vesicles could regulate plasma glucose into a normal value on the mouse model with type I diabetes. In addition to pillar[5]arene, pillar[6]arene could also be used to prepare vesicles. For example, a pillar[6]arene derivative (WP6) with good solubility in water was synthesized by Huang and coworkers, which formed vesicles with pyridinium salt (Fig. 4) [104]. The solubility of WP6 could be adjusted by changing pH, since there were 12 carboxylate groups on both rims of WP6. Hence, the obtained vesicles could transform into nanotubes reversibly by adjusting pH values. Compared to pillar[5]arene and pillar[6]arene, supramolecular vesicles based on pillar[7]arene are relatively fewer. Huang and coworkers reported an interesting example of pillar[7]arene-guest supramolecular vesicles [105]. A water-soluble pillar[7]arene (WP7) bearing 14 anionic carboxylate groups was synthesized, and pillar[7]arene-guest supramolecular vesicles were constructed by the complexation between WP7 and a paraquat derivative spontaneously in water.

Fig. 4
figure 4

Schematic illustration of the formation of WP6/pyridinium vesicles with pH responsiveness. (Reproduced with permission from [104]. Copyright 2012, American Chemical Society)

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3 Stimulus Responsiveness of Host-Guest Supramolecular Vesicles

Host-guest supramolecular vesicles are fabricated by host-guest supramolecular amphiphiles via host-guest recognition, endowing them with high sensitivity to various stimuli owing to dynamic association/dissociation equilibrium of host-guest inclusion complexes. Because of the structure difference between host and guest molecules, host-guest supramolecular vesicles could respond to different stimuli such as pH value, enzyme, light, reduction, and so on, as discussed below.

3.1 pH Responsiveness

The accumulation of lactic acid in tumor tissues caused by vigorous metabolism and proliferation of tumor cells makes extracellular pH value of tumor cells (6~7) lower than that of normal cells (~7.4) [106]. Active transport of antitumor drug or bioimaging molecules could be realized based on this difference of pH value between tumor tissues and normal tissues. Hence, a lot of effort is invested to design pH responsive host-guest supramolecular vesicles. This type of vesicles is relatively stable under normal pH value, while they would dissociate upon the decrease of pH value accompanied with the release of antitumor drugs or bioimaging molecules.

Huang and coworkers reported pH responsive pillar[6]arene-guest supramolecular vesicles [107]. The water-soluble pillar[6]arene derivative (WP6) and a hydrophilic 4,4′-bipyridinium derivative were synthesized. They found that WP6 and the guest molecule could form nanovesicles on account of the host-guest recognition. The obtained vesicles could transfer into micelles upon the decrease of pH value to around 6, owing to the dissociation of the inclusion complex. As a hydrophilic fluorescent molecule, calcein could be encapsulated into the interior of the vesicles, while the release of calcein was triggered by the decrease of pH value. Similarly, pH responsive vesicles based on tryptophan-modified pillar[5]arene (TP5) and galactose derivative were investigated by Pei and coworkers [108]. The obtained vesicles were prepared via the host-guest interaction between TP5 and galactose derivative, which were used to load DOX effectively. DOX could be released from the vesicles rapidly at acidic environment, showing good responsiveness to pH value. Wang and coworkers constructed a pH responsive vesicle system from water-soluble phosphate-based pillar[6]arene (WP6P) and pyridinium bromide guest [96]. After supramolecular complexation, supramolecular hollow vesicles (WP6P ⊃ G) were obtained in aqueous environment. Hydrophilic anticancer drug mitoxantrone (MTZ) was efficiently loaded into WP6P ⊃ G vesicles, which could be released controllably at lower pH value, illustrating the potential application in drug delivery (Fig. 5).

Fig. 5
figure 5

Schematic illustration of the formation of WP6P/G vesicle and its application in drug delivery. (Reproduced with permission from [96]. Copyright 2016, American Chemical Society)

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3.2 Enzyme Responsiveness

Enzyme is a kind of protein with highly effective catalytic activity, which correlates with almost all metabolic reactions in human body, playing an essential role in most physiological activities. Hence, it is significant to study host-guest supramolecular vesicles with enzyme responsiveness. Stable supramolecular vesicles with an average diameter around 230 nm based on β-cyclodextrin dimer and paclitaxel were successfully constructed by Xie and coworkers (Fig. 6) [109]. Such vesicles could turn into solid nanoparticles upon the addition of ɑ-amylase owing to the digestion of β-cyclodextrin by ɑ-amylase. Interestingly, nanoparticles could transfer back into vesicles again when additional β-cyclodextrin was added into this system. In addition, this vesicle system was used to load and release hydrophilic indocyanine green molecule and hydrophobic DOX effectively. Liu and coworkers presented enzyme responsive vesicles prepared based on p-sulfonatocalixarene and protamine [82]. Non-amphiphilic p-sulfonatocalixarene and non-amphiphilic protamine were used to construct supra-amphiphilic vesicles in water by a feasible strategy. The dissociation of the vesicles was triggered by trypsin, since trypsin is capable of cutting off protamine into amino acid and peptide segments. More importantly, the vesicles exhibit enzyme responsiveness at high-concentration trypsin site, certified by cell experiments and preliminary fluorescence imaging in mice.

Fig. 6
figure 6

Schematic illustration of the formation of β-cyclodextrin dimmer and paclitaxel vesicle and its enzyme responsiveness. (Reproduced with permission from [109]. Copyright 2017, American Chemical Society)

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3.3 Photo Responsiveness

Light is a clean, noninvasive, remote controllable, and temporal stimulus that associates with numerous applications. It is of great importance to study photoresponsive host-guest supramolecular vesicles. The trans-cis isomerization of azobenzene moiety could be realized under ultraviolet light, which has been utilized extensively in the construction of photoresponsive host-guest supramolecular vesicles. For instance, Wang and coworkers developed photoresponsive host-guest supramolecular vesicles based on the water-soluble pillar[6]arene (WP6) and an azobenzene derivative, which exhibited excellent reversible photo responsiveness [110]. These supramolecular vesicles could be collapsed upon the irradiation with 365 nm UV light, while vesicles could be formed again by the irradiation with visible light. This is reasonable, since the trans structure of the azobenzene guest could form the inclusion complex with WP6, while there is almost no encapsulation behavior between cis structure of the azobenzene guest and WP6. Photoresponsive supramolecular vesicles prepared by β-cyclodextrin and a hydrophobic prodrug were recently reported by Jiang and coworkers (Fig. 7) [111]. Phenytoin and azobenzene were conjugated together to form the azo-phenytoin prodrug, which was then encapsulated by β-cyclodextrin to form a supra-amphiphile with hydrophilic head and hydrophobic tail. The supra-amphiphile could self-assemble into vesicles spontaneously in water. The β-cyclodextrin/azo-phenytoin vesicles would be changed to irregular particles under UV light irradiation, showing excellent photo responsiveness.

Fig. 7
figure 7

Self-assembly of β-cyclodextrin and azobenzene-modified prodrug with dual responsiveness. (Reproduced with permission from [111]. Copyright 2017, The Royal Society of Chemistry)

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3.4 Reduction Responsiveness

The change of the potential in cells has very important effect on physiological activity of living systems. Thus, it is essential to study supramolecular host-guest vesicles with reduction responsiveness. A useful antioxidant in human body is glutathione, which can clear free radicals. The concentration of glutathione in many tumor cells is higher than that in normal cells, giving us the opportunity to fabricate glutathione responsive host-guest vesicles. In order to prepare host-guest vesicles with glutathione responsiveness, Pei and coworkers synthesized ferrocenecarboxylic acid modified pillar[5]arene (FACP5) and a galactose derivative as the guest [112]. Then, supramolecular vesicles based on FACP5 and galactose guest were fabricated. DOX could be loaded into the obtained vesicles effectively. More importantly, the vesicles could be collapsed with the release of DOX when transforming hydrophilic ferrocenium group to hydrophobic ferrocene once FACP5 reduced by glutathione. Huang and coworkers also established reduction responsive pillar[5]arene-based supramolecular vesicles [113]. Poly(ethylene glycol) modified pillar[5]arene (P5-PEG-Biotin) and viologen terminator grafted poly(caprolactone) (PCL-C2V) were synthesized and used to construct P5-PEG-Biotin/PCL-C2V vesicles in water. P5-PEG-Biotin/PCL-C2V vesicles could be applied to deliver DOX as well. P5-PEG-Biotin/PCL-C2V vesicles could be disassembled along with the DOX release after the internalization by cancer cells, owing to the breaking of the host-guest interaction through the reduction of the viologen group into cationic radical structure by intracellular reductive agents.

3.5 Glucose Responsiveness

Glucose is an indispensable substance in human body, which participates in the metabolism process of life activities. However, high glucose concentration in blood may lead to diabetes mellitus. Hence, it is necessary to design and fabricate host-guest supramolecular vesicles with glucose responsiveness, aiming to improve the life quality of diabetic patients. Glucose responsive supramolecular vesicles were successfully constructed by Wang and coworkers [114]. The water-soluble pillar[5]arene (WP5) and a pyridylboronic acid modified guest molecule were well-designed and synthesized firstly. WP5 could recognize and encapsulate the guest molecule to form supramolecular amphiphile, and such supra-amphiphile could further self-assemble into higher-order vesicles in aqueous media. The obtained vesicles could respond to D-glucose sensitively, since pyridylboronic acid modified on the guest molecule binds D-glucose with high binding affinity. Fluorescein isothiocyanate–labeled insulin as a model molecule was loaded into the vesicles. The vesicles could be collapsed along with the insulin release upon D-glucose stimulus, making the vesicles a suitable system for the insulin delivery.

3.6 Multiple Responsiveness

The microenvironment inside our human body is very sophisticated, having a lot of indicators. Therefore, it is useful to construct host-guest supramolecular vesicles with multiple responsiveness for biomimetics. Wang and coworkers fabricated triple stimuli responsive pillar[6]arene vesicles (Fig. 8) [115]. The water-soluble pillar[6]arene (WP6) and a pyridinium derivative as the guest molecule were synthesized firstly. WP6/pyridinium supramolecular vesicles were obtained through the host-guest interaction. Calcein as the model substrate could be encapsulated into the vesicles efficiently. The disruption of calcein-loaded vesicles for the calcein release could be realized by decreasing pH or Ca2+ addition. Moreover, the vesicles would be changed to giant vesicles upon temperature increase, which may have potential applications in biomimetic or bioimaging. Five stimuli responsive supramolecular vesicles were reported by Du and coworkers very recently [116]. The vesicles were co-assembled from supramolecular amphiphile formed between carboxylate-substituted pillar[6]arene (CPA[6]) and disulfide-linked benzimidazolium. The vesicles could be disintegrated for the release of encapsulated drugs under different stimuli including glutathione, pH, CO2, Zn2+, and hexanediamine. The responsiveness of the vesicles to glutathione was ascribed to the cleavage of disulfide linkage in the inclusion complex by glutathione. CO2 addition and acidic pH value had the similar effect on the vesicles, since CO2 could induce acidic pH value. CPA[6] could be protonated under acidic pH value, leading to the extrusion of the guest molecule from protonated CPA[6]. Zn2+ could chelate with the carboxylate groups on CPA[6], disrupting the host-guest inclusion complex. As a competitive guest, hexanediamine could bind with CPA[6] more tightly than the pyridinium guest, dissociating the vesicles.

Fig. 8
figure 8

Schematic illustration of the formation of WP6/pyridinium vesicles with multiple stimulus responsiveness. (Reproduced with permission from [115]. Copyright 2014, American Chemical Society)

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4 Applications of Host-Guest Supramolecular Vesicles

4.1 Drug Delivery

One of the main applications of host-guest supramolecular vesicles is drug delivery. Host-guest supramolecular vesicles with several hundreds of nanometers could accumulate in tumor sites through enhanced permeability and retention (EPR) effect, making them suitable for drug delivery [117, 118]. More importantly, host-guest supramolecular vesicles are relatively sensitive, which could respond to stimuli inside cancer cells, leading to the drug release simultaneously. Hydrophilic anticancer drugs such as DOX and MTZ are often used as the model drugs for drug delivery, since they could be encapsulated into the interior of supramolecular vesicles. DOX was successfully loaded into supramolecular vesicles made from β-cyclodextrin and bis-adamantane derivative, as reported by Gopidas and coworkers [119]. Bright red luminescence of the vesicles was observed under confocal laser scanning microscope on account of the encapsulation of DOX inside the vesicles with the loading efficiency of 7.06%. Moreover, DOX could be released with the disassembly of the vesicles by adding adamantane carboxylate as the competitive guest into the vesicular system. Wang and coworkers reported DOX-loaded supramolecular vesicles based on water-soluble pillar[5]arene (WP5) and boron-dipyrromethene (BODIPY) derivative [120]. The encapsulation efficiency of DOX was about 14%, and DOX could be released rapidly under acid environment. The cytotoxicity of DOX-loaded vesicles was remarkable against A549 cancer cells upon the light irradiation to generate singlet oxygen produced by BODIPY, showing chemo- and photodynamic therapy at the same time. In addition, DOX-loaded vesicles could be localized in lysosomes of cancer cells, evaluated by confocal laser scanning microscope.

MTZ has good therapeutic effects to various cancers such as malignant lymphoma, breast cancer, and acute leukemia by interfering the DNA synthesis. Hence, it is also a common drug model in the drug delivery. Wang and coworkers conducted some interesting research in this area. They developed MTZ-loaded supramolecular vesicles, where the amphiphile formed by water-soluble pillar[6]arene (WP6) and ferrocene derivative could self-assemble into supramolecular binary vesicles [121]. MTZ was loaded into the supramolecular vesicles with 11.2% encapsulation efficacy. The toxicity of MTZ to normal cells could be reduced by loading into the vesicles. Moreover, MTZ-loaded vesicles could be internalized by cancer cells, leading to the disassembly for the MTZ release.

In addition to anticancer drugs, DNA could also be delivered by host-guest supramolecular vesicles. Feng and coworkers exhibited supramolecular vesicles for the co-delivery of DNA and DOX [122]. The inclusion complex between tris(2-aminoethyl)amine modified β-cyclodextrin-centered hyperbranched polyglycerol (CD-HPG-TAEA) and adamantane-terminated octadecane (C18-AD) was used to build supramolecular vesicles. DOX could bind with DNA through electrostatic attraction, and further be loaded into the vesicles together. In addition, the dissociation of the vesicles for the release of DOX and DNA could be realized upon the vesicle uptake by cancer cells, owing to the protonation of amine groups on CD-HPG-TAEA.

4.2 Bioimaging and Sensing

In addition to drug delivery, host-guest supramolecular vesicles have also been widely used in bioimaging and sensing. Zhao and coworkers reported supramolecular vesicles based on pillar[5]arene for bioimaging (Fig. 9) [123]. Four different amphiphilic pillar[5]arene derivatives bearing ethylene glycol groups were synthesized and systematically studied. Tadpole-like amphiphilic pillararene and bola-like amphiphilic pillararene could encapsulate a water-soluble viologen derivative, and the obtained complexes could self-assemble into binary vesicles. Hydrophilic fluorescent dye rhodamine B was loaded into the interior of these vesicles effectively, imaging green and red colors in HeLa cells. Tadpole-like amphiphilic pillararenes could also self-assemble into binary vesicles. These vesicles were capable of delivering hydrophobic dye fluorescein isothiocyanate and hydrophilic fluorescent dye rhodamine B at the same time, since fluorescein isothiocyanate was located in the hydrophobic membranes of the vesicles while rhodamine B was in the hydrophilic cavity of the vesicles. Bioimaging of fluorescein isothiocyanate and rhodamine B co-loaded vesicles was confirmed by confocal laser scanning microscope, showing green and red colors in HeLa cells.

Fig. 9
figure 9

Schematic illustration of the formation of pillararene-based assemblies for bioimaging [123]. (Copyright 2013, American Chemical Society)

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Huang and coworkers developed host-guest supramolecular vesicles for dual fluorescent sensing (Fig. 10) [19]. A bola-type supramolecular amphiphile based on the water-soluble pillar[5]arene (WP5) and quinquephenyl guest molecule was prepared. The guest molecule could self-assemble into thin sheets, and the thin sheets transformed into vesicles upon the addition of WP5 where bola-type supramolecular amphiphile was formed. The fluorescence of the guest molecule increased dramatically in this transformation process, because the electronic coupling of the quinquephenyl aromatic ring of the guest molecule could be suppressed by WP5. Furthermore, the obtained vesicles could respond to a trace amount of paraquat and H+, and thus they were used to detect paraquat and H+ through fluorescent sensing. The fluorescence of the vesicles was almost disappeared under the addition of paraquat, since the binding constant between WP5 and paraquat was higher than that between WP5 and the guest molecule. H+ could also decrease the fluorescence intensity of the vesicles markedly due to the dissociation of bola-type supramolecular amphiphile.

Fig. 10
figure 10

Schematic illustration of the formation of bola-type supra-amphiphiles [19]. (Copyright 2014, The Royal Society of Chemistry)

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5 Summary and Outlook

Responsive materials play vital roles in the design of smart cargo delivery systems and soft robotics. The development of supramolecular chemistry provides diverse opportunities for the fabrication of responsive materials. Host-guest interactions normally reply on noncovalent forces such as hydrogen bonding interaction, coordination, aromatic force, and electrostatic interaction. Thus, host-guest interactions between host and guest molecules are capable of integrating two or more species into one building block. The resultant building blocks are utilized to construct architectures at all scales such as nanotubes, nanowires, micelles, gels, and vesicles. Host-guest interactions endow these architectures with enhanced sensitivity to internal and external stimuli, which are favorable to the fabrication of smart materials.

In this chapter, we focus on the discussions about vesicular structures self-assembled from host-guest amphiphiles. Vesicles with flexible membranes are suitable systems for loading and delivering both hydrophobic and hydrophilic cargos. Nanosized vesicles could reply on the EPR effect to be internalized within cells, allowing for drug delivery and bioimaging applications. By highlighting recent developments in this research field, different kinds of macrocyclic hosts including cyclodextrins, cucurbiturils, calixarenes, and pillararenes have been employed to construct host-guest supramolecular vesicles. Based on delicate design, these vesicles could be responsive to specific stimuli such as pH, photo irradiation, enzyme, and temperature, where topological variation, disassociation, and re-assembly of vesicles have been observed. These studies contribute greatly to the design of smart materials for advanced applications such as in drug delivery, imaging, and sensing.

Despite these promising developments, we believe that future investigations may be focused more on two aspects, which are the structure-property relationship and the extension of advanced application scope. Although various kinds of host and guest molecules with specific structures have been proven effective in constructing vesicles, it is still difficult to precisely predict the self-assembled topology during molecular design, because host-guest amphiphiles are different to the conventional amphiphiles of which self-assemblies could usually be predicted by the theory of molecular packing parameters. Thus, more endeavors are expected to address this challenge. Another challenge is how we could accomplish valid applications of host-guest supramolecular vesicles. Although some vesicles have been applied in biomedical applications, they still possess numerous disadvantages as compared with well-studied liposomes and polymersomes in terms of the biocompatibility and stability during long-term circulation. Therefore, how to address these disadvantages and fully utilize stimulus responsiveness is a significant task.