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Functional Supramolecular Polymers for Biomedical Applications Ruijiao Dong, Yongfeng Zhou, Xiaohua Huang, Xinyuan Zhu,* Yunfeng Lu, and Jian Shen* In 1978, Lehn firstly put forward the concept of supramolecular chemistry referring to the chemistry beyond the molecule, which aims at constructing highly complex, functional systems from building blocks held together through intermolecular non-covalent interactions.[1–3] As an elegant bridge between polymer science and supramolecular chemistry, supramolecular polymers have attracted much interest in various fields.[4–6] According to their formation mechanism, supramolecular polymers can be classified into two major types: one type is random-coil supramolecular polymer without internal order, in close analogy to conventional covalent polymers; the other type is ordered supramolecular polymers with shape-persistent nanostructure.[7] In general, strong and directional non-covalent interactions between the molecular building blocks not only recreate traditional polymeric properties, but also bring about some unique functionalities that do not exist in covalent polymers (e.g., molecular order and dynamics), thereby achieving their specific functions.[8] To date, various types of non-covalent interactions, including multiple hydrogen bonding, metal coordination, π−π stacking and host–guest interactions, have been widely employed to fabricate a large number of supramolecular polymers with versatile topological features and distinct physicochemical properties.[9–14] These reversible non-covalent connections not only endow supramolecular polymers with the ability to undergo reversible switching of structure, morphology, and properties under exposure to certain external stimuli,[15] but also provide a flexible and robust platform for the preparation of functional supramolecular polymeric materials and smart supramolecular devices. Nowadays, functional supramolecular polymers play a crucial role in material science, owing to their dynamically switchable structure and exceptional functions. Especially, a rapidly increasing number of publications related to the preparation of functional supramolecular polymers and their biomedical applications have been reported in recent years. Herein, we expect that, by our detailed review of current research achievements in this field, the important position and bright prospect of functional supramolecular polymers as excellent candidates for developing intelligent supramolecular biomedical materials are clearly presented.

As a novel class of dynamic and non-covalent polymers, supramolecular polymers not only display specific structural and physicochemical properties, but also have the ability to undergo reversible changes of structure, shape, and function in response to diverse external stimuli, making them promising candidates for widespread applications ranging from academic research to industrial fields. By an elegant combination of dynamic/reversible structures with exceptional functions, functional supramolecular polymers are attracting increasing attention in various fields. In particular, functional supramolecular polymers offer several unique advantages, including inherent degradable polymer backbones, smart responsiveness to various biological stimuli, and the ease for the incorporation of multiple biofunctionalities (e.g., targeting and bioactivity), thereby showing great potential for a wide range of applications in the biomedical field. In this Review, the trends and representative achievements in the design and synthesis of supramolecular polymers with specific functions are summarized, as well as their wide-ranging biomedical applications such as drug delivery, gene transfection, protein delivery, bioimaging and diagnosis, tissue engineering, and biomimetic chemistry. These achievements further inspire persistent efforts in an emerging interdisciplinary research area of supramolecular chemistry, polymer science, material science, biomedical engineering, and nanotechnology.

1. Introduction In living systems, a variety of supramolecular structures play an important role in maintaining life, such as double-helix DNA, functional protein domains, microtubules, and microfilaments. Dr. R. J. Dong, Prof. Y. F. Zhou, Prof. X. Y. Zhu, Prof. Y. F. Lu School of Chemistry and Chemical Engineering State Key Laboratory of Metal Matrix Composites Shanghai Jiao Tong University 800 Dongchuan Road, Shanghai 200240, PR China E-mail: [email protected] Prof. X. H. Huang, Prof. J. Shen Jiangsu Collaborative Innovation Center of Biomedical Functional Materials Jiangsu Key Laboratory of Biomedical Materials College of Chemistry and Materials Science Nanjing Normal University Nanjing 210046, PR China E-mail: [email protected] Prof. Y. F. Lu Department of Chemical and Biomolecular Engineering University of California Los Angeles, California 90095, USA

DOI: 10.1002/adma.201402975

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In this Review, we provide a summary of the design and synthesis, and the properties and functions of functional supramolecular polymers, as well as their wide range of application in the biomedical field including drug delivery, gene transfection, protein delivery, bioimaging and diagnosis, tissue engineering, and biomimetic chemistry. We try to illustrate the general concepts and structure–property–function relationship of functional supramolecular polymers, as well as their widespread bioapplications, further casting some light on the following work in this emerging research area.

Ruijiao Dong completed his B.Sc. degree in Materials Science at Wuhan Textile University and his M.Sc. degree in Polymer Chemistry at Donghua University. In 2009, he joined Prof. Xinyuan Zhu’s group as a Ph.D. student in the Department of Chemistry at Shanghai Jiao Tong University. Currently, he is working on the synthesis and application of functional

2. Design and Synthesis There are two key structural parameters for the design and synthesis of functional supramolecular polymers for biomedical applications involving non-covalent interactions and topological structures. First, different types of non-covalent interactions such as multiple hydrogen bonding, metal coordination, π−π stacking and host–guest interactions, display-distinct association features and diverse stimuli-responsive properties, which endow the resulting supramolecular polymers with variable functions. That is, non-covalent interactions have an extremely important effect on the release behavior and biological activity of the resulting supramolecular delivery vehicles in the human body. Second, the topological structures that are highly dependent on the degree of functionality of the building blocks, play a crucial role in determining the macroscopic performance and biomedical application prospect of the resultant supramolecular polymers. Therefore, the types of non-covalent interactions and the degree of functionality of the building blocks greatly determine the properties and functions of supramolecular polymers. As a result, functional supramolecular polymers for biomedical applications can be acquired by judicious selection of non-covalent interactions and building blocks.

2.1. Non-covalent Interactions Using a self-complementary unit (A–A) or a hetero-complementary couple (A–B), it is possible to form a large number of supramolecular polymers with different topological structures in the case of complementary couples.[4] Supramolecular polymers can be fabricated through the reversible association of multi-functionalized components; therefore, the degree of polymerization obviously depends on the strength of association of non-covalent interactions, the purity of the monomers, and the concentration of the solution.[16] In particular, a higher association constant between the building blocks is an essential precondition to obtain supramolecular polymers with a high molecular weight. Hitherto, various non-covalent interactions involving multiple hydrogen bonding, metal coordination, π−π stacking, and host–guest interactions, as well as integrated non-covalent interactions, have been utilized as the driving forces to prepare versatile functional supramolecular polymers (Figure 1). Multiple hydrogen bonding plays an important role in supramolecular chemistry due to its directionality and diversity, thereby affording enhanced stability and specificity for the

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supramolecular polymers. Xinyuan Zhu completed his B.Sc. and M.Sc. degrees in Materials Science at Donghua University, and obtained his Ph.D. degree in Materials Science at Shanghai Jiao Tong University in China. Following academic appointments at Shanghai Jiao Tong University, he joined the BASF research laboratory at ISIS in Strasbourg as a post-doctoral researcher. He came back to Shanghai Jiao Tong University and became a full professor in 2005. His scientific interests focus on functional polymers. Jian Shen received his B.Sc. degree in Polymer Chemistry from Nanjing University, China in 1982. He obtained his Ph.D. in Polymer Chemistry at Nanjing University of Science and Technology in 2005. Now, he is a professor in the Research Center of Surface and College of Chemistry and Materials Science, Nanjing Normal University. His current research interests include molecule design and synthesis of novel anticoagulant materials. resulting hydrogen-bonded supramolecular polymers.[5,7,17,18] In general, these hydrogen-bonded supramolecular polymers possess typical pH-responsiveness, and can thus be used as promising carriers for controlled drug delivery in acidic tumor tissues. The metal coordination exhibits a tunable coordination binding strength, as well as exceptional redox and photophysical properties, originating from the metal ions and ligands. It facilitates construction of stimuli-responsive metallo-supramolecular polymers for potential applications in the field of biodetection devices.[9,10,19–21] π−π stacking, which results from

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REVIEW Figure 1. Different non-covalent interactions for the construction of supramolecular polymers: A) multiple hydrogen bonding, B) metal coordination, C) π−π stacking as well, and D) host–guest interaction based on cyclodextrin, crown ether, cucurbit[n]uril, calix[n]arene and pillar[n]arene.

intermolecular overlapping of p-orbitals of π-conjugated systems, is relatively weak and non-directional in apolar solvents. Due to its intrinsic properties of π-conjugated monomers, π−π stacking is advantageous for the preparation of photoactive, electroactive, and liquid-crystalline supramolecular polymers that can be applied for bioimaging and diagnosis.[22,23] As compared with other non-covalent interactions, host–guest interactions based on cyclodextrin (CD),[11] crown ether,[12] calixarene,[13,24] cucurbit[n]uril[14,25] and pillar[n]arene,[26] which possesses high strength, specific recognition and versatile host–guest couples, are widely utilized to develop diverse supramolecular polymers for a wide range of biomedical applications. Generally, supramolecular polymers formed by single noncovalent interactions exhibit several drawbacks, such as low degree of polymerization, poor stability, simple structure, and single function. Therefore, the combination of multiple noncovalent interactions in the same supramolecular polymers is a valuable tool for increasing their degree of polymerization and stability.[27–30] Especially, the cooperative effect of different

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non-covalent interactions further leads to the generation of complicated and hierarchical supramolecular structures, and then the resulting supramolecular polymers will be endowed with multiple properties and smart responses under different stimuli. Furthermore, it is expected that multifunctional supramolecular polymers can be obtained using integrated noncovalent interactions, which might be very attractive for their bioapplications.

2.2. Topological Structures Molecular topological structures, which are highly related to the numbers of recognition sites of building blocks, have an important effect on the physical/chemical properties and functions of the resulting supramolecular polymers. Therefore, these functional supramolecular polymers with different topological structures for biomedical applications not only show variable biological activities, but also display distinct therapeutic efficacy

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in the treatment of various diseases. According to molecular topological features, supramolecular polymers can be divided into the following four major classes: supramolecular linear polymers, supramolecular dendritic polymers, supramolecular star-shaped polymers, and supramolecular crosslinked polymers. As a class of 1D supramolecular polymeric structures, supramolecular linear polymers not only possess the specific physical/chemical properties of traditional polymers, such as low solubility, high viscosity, strong intermolecular entanglement, and only two terminal groups, but also they exhibit a dynamic/ tunable nature. On the basis of the architectures, supramolecular linear polymers can be classified into three major types, such as supramolecular homopolymers,[31–38] supramolecular alternating copolymers,[39–45] and supramolecular block copolymers[46–56] (Figure 2). Generally, supramolecular linear polymers can be produced from ditopic monomeric species with self-complementary or hetero-complementary recognition sites. The architectures of supramolecular linear polymers greatly depend on the type and characteristics of the recognition units in ditopic monomers. Two approaches have been established to fabricate supramolecular linear polymers: one is a single-monomer methodology for the preparation of supramolecular homopolymers, and the other is a double-monomer methodology for the preparation of supramolecular alternating copolymers. Notably, these supramolecular linear polymers that are formed from small-molecule-based building blocks show predominantly fiber-like structures, and even a peculiar helical secondary structure can be produced through incorporation of chiral groups into building blocks.[57–61] In contrast, supramolecular block copolymers is a class of special supramolecular linear structures consisting of two or more chemically distinct linear building blocks, including supramolecular diblock copolymers[47–51,56] and supramolecular triblock

Figure 2. Supramolecular linear polymers with different structures: A) supramolecular homopolymer, B) supramolecular alternating copolymer, C) supramolecular diblock copolymer, and D) supramolecular triblock copolymer.

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Figure 3. Supramolecular dendritic polymers with distinct topological features: A) supramolecular dendrimer, B) supramolecular dendronized polymer, C) supramolecular hyperbranched polymer, D) supramolecular linear-dendritic block copolymer, E) supramolecular Janus dendritic polymer, and F) supramolecular dendritic multiarm copolymer. Reproduced with permission.[62] Copyright 2014, American Chemical Society.

copolymers.[52–55] Supramolecular block polymers can further self-assemble into various impressive supramolecular structures at all scales and dimensions, and thus display great potential as a promising candidate in the biomedical field. Supramolecular dendritic polymers, by a perfect combination of the advantages of supramolecular polymers with those of dendritic polymers, are a promising class of 3D, non-covalently bonded, highly branched globular macromolecules.[62] In comparison with supramolecular linear polymers, supramolecular dendritic polymers exhibit distinct physicochemical properties such as high solubility, low viscosity, weak molecular entanglement, and numerous terminal units. In view of the topological features, supramolecular dendritic polymers can be systematically divided into the following six main subclasses: supramolecular dendrimers,[63–67] supramolecular dendronized polymers,[68–71] supramolecular hyperbranched polymers,[72–75] supramolecular linear–dendritic block copolymers,[76–78] supramolecular Janus dendritic polymers,[79–81] and supramolecular dendritic multiarm copolymers,[82,83] which display controllable morphologies, unique structures, and specific functions (Figure 3). Unlike conventional dendritic polymers, supramolecular dendritic polymers afford several particular advantages: facile synthesis and purification, switchable structures and shapes, and smart stimuli-responsiveness. Benefiting from their globular topological structure and plenty of inner cavities, the resultant supramolecular dendritic polymers are capable of encapsulating drugs, therapeutic genes, or proteins via various non-covalent interactions, making them novel candidates for controlled drug/gene/protein delivery. Supramolecular star-shaped polymers with three or more arms radiating from a core have attracted significant attention in a wide range of fields due to their condensed structure, non-linear shape, and multiple chain ends per macromolecule. In recent years, a variety of supramolecular star-shaped polymers have been prepared by self-assembly of suitable polymeric building blocks using non-covalent interactions. In terms of the symmetry properties of supramolecular star-shaped polymers, they can be classified as supramolecular homoarm star-shaped

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Figure 4. Supramolecular star-shaped polymers with different symmetry properties: A) supramolecular homoarm star-shaped polymer and B) supramolecular miktoarm star-shaped polymer.

polymers[84–92] and supramolecular miktoarm star-shaped polymers[93–95] (Figure 4). For the supramolecular homoarm starshaped polymers, there are two general synthesis strategies: template-directed synthesis and untemplated synthesis. Typically, supramolecular miktoarm star-shaped polymers refer to asymmetric supramolecular star-shaped polymers with three or more different arms radiating from one core. Supramolecular miktoarm star-shaped polymers are fabricated through the supramolecular coupling of three or more structurally distinct polymeric building blocks using hetero-complementary recognition motifs. In contrast to the homoarm star-shaped ones, the asymmetric structure affords them with fascinating hierarchical architectures (e.g., multicompartment micelles), and thus the resulting supramolecular assembly nanostructures are capable of loading diverse therapeutic agents in different compartments, further showing great potential in the field of drug and gene co-delivery. As a new class of intelligent polymeric materials, supramolecular crosslinked polymers with 3D network structures not only possess the mechanical properties gained from the polymeric building blocks, but also show stimuli-responsiveness and processability, which are inherent to the supramolecular units used in the crosslinking. The use of various non-covalent interactions, such as hydrogen bonding, salt bridges, metal– ligand coordination, and host–guest interactions endows the crosslinks with a reversible nature, and thus the macroscopic properties of the resulting supramolecular crosslinked polymers can be reversibly switched in response to various external stimuli. There are two distinct synthesis techniques for generating supramolecular crosslinked polymers based on the types of building block: conventional polymeric scaffolds[96–102] and supramolecular polymer blocks[103–108] (Figure 5). The supramolecular crosslinking of the polymeric building blocks dramatically reduces the structural flexibility and changes the macroscopic morphologies/properties, leading to the formation of supramolecular polymeric organo- and hydrogels. In particular, the resultant supramolecular polymeric hydrogels display attractive performances, such as water-retention ability, drug-encapsulation capability, stimuli-responsiveness, and selfhealing behavior, and can thus be used as flexible and smart scaffolds for tissue engineering and controlled drug delivery.

3. Properties and Functions

responsiveness and processability arising from the noncovalent units. In particular, the use of specific non-covalent interactions between molecular building blocks can endow the resulting supramolecular polymeric materials with rich dynamic behaviors and high degrees of structural order. Generally, the performance and functionality of supramolecular polymers can be acquired in two different ways. In one case, the incorporation of functional components into original building blocks will bestow the resulting supramolecular polymers with the expected functions, and such functionality mainly derives from the intrinsic molecular structures of the building blocks. On the other hand, the cooperative self-assembly of the building blocks is capable of generating well-defined supramolecular polymers with highly ordered nanostructures, leading to unexpected functions beyond molecular structure. In order to realize their application in a wide range of applications in the biomedical field, the resultant supramolecular polymers should have the following basic properties: aqueous compatibility, biodegradability and biocompatibility, stimuli-responsiveness, targeting, bioactivity, and other specific functions. In this section, we thoroughly elaborate these essential properties or functions of supramolecular polymers for biomedical applications. 3.1. Aqueous Compatibility

As a novel class of dynamic and non-covalent macromolecules, supramolecular polymers display not only physicochemical properties similar to covalent polymers, but also the stimuli

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Figure 5. 3D supramolecular crosslinked polymers based on different types of building blocks, including: A) conventional polymeric scaffolds and B) supramolecular polymer blocks.

It’s well-known that water plays a key role in maintaining life and health, and also provides an indispensable medium

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for a wide range of biochemical reactions and biological processes in various living organisms. In nature, there are a large number of aqueous compatible supramolecular nanostructures derived from the self-assembly of natural small molecules in an aqueous medium. Inspired by nature, many sorts of aqueouscompatible supramolecular polymers have been widely developed using different supramolecular approaches, which have wide applications in various applications in the biomedical field. By this token, aqueous compatibility is an essential prerequisite to supramolecular polymers for biomedical applications. Currently, supramolecular polymers with excellent aqueous compatibility mainly contain two major categories: water-soluble supramolecular polymers through specific non-covalent interactions and amphiphilic supramolecular assemblies formed by aqueous self-assembly (Figure 6). Hydrophilic macrocyclic molecules such as CD, cucurbit[n] uril, and hydrophilic calix[n]arene derivatives (e.g., sulfonatocalixarene), are capable of recognizing the specific guest species to form rotaxane-like or catenane-like inclusion complexes, which can be widely employed to construct water-soluble supramolecular polymers via host–guest interactions in aqueous solution (Figure 6A). Among them, CD can readily include various hydrophobic molecules (e.g., adamantane, azobenzene, ferrocene, stilbene, etc.) inside its hydrophobic interior in water. A variety of hydrophilic supramolecular polymers with distinct topological structures and physicochemical properties have been successfully constructed based on CD-based host– guest chemistry such as supramolecular polyrotaxane, linear or dendritic supramolecular polymers, supramolecular hydrogels, and so forth. These CD-based supramolecular polymers

not only possess favorable biodegradability and biocompatibility, but also can rapidly respond to versatile external stimuli (e.g., pH, temperature, light and redox agents), showing great potential in the fields of drug delivery, gene transfection, and tissue engineering.[11,109–111] In contrast, curbit[n]uril has good selectivity and strong binding affinity to cationic guest species in water to form a host–guest inclusion complex. Since curbit[8]uril has the ability to encapsulate two guest molecules in its cavity to form stable ternary complexes, such a curbit[8] uril-based host–guest recognition motif has been extensively used to prepare water-soluble supramolecular polymers.[14,112] Also, p-sulfonatocalix[4]-arene as a hydrophilic calix[n]arene derivative can be employed to build versatile stimuli-responsive supramolecular polymers in aqueous solution.[113–115] In addition, aqueous-compatible supramolecular polymers can be also fabricated by aqueous self-assembly of amphiphilic building blocks, including conventional amphiphiles and supramolecular amphiphiles (Figure 6B). In conventional amphiphiles, the hydrophilic and hydrophobic parts are linked together by covalent bonds. Owing to their amphiphilic nature, these conventional amphiphiles are capable of self-assembly in aqueous solution to form diversified well-defined supramolecular assemblies, such as micelles, vesicles, and fibers.[116–118] The architectures, properties and functions of the resulting supramolecular assemblies are remarkably dependent on the intrinsic structure of the amphiphiles. In sharp contrast to covalently bonded amphiphiles, supramolecular amphiphiles are constructed by supramolecular coupling of hydrophilic and hydrophobic building blocks (e.g., small-molecule blocks or polymeric blocks) based on various non-covalent interactions.[119–121] In supramolecular amphiphiles, functional components can be facilely incorporated into the amphiphiles using the non-covalent approach, thereby avoiding tedious chemical synthesis and improving the preparation procedure. The resultant supramolecular assemblies formed from supramolecular amphiphiles not only hold inherent structures and properties of conventional amphiphilic assemblies, but also exhibit distinct hierarchical architectures as well as dynamically switchable functions in response to various external stimuli. Because of their abundant hydrophobic or hydrophilic interior cavities and smart responsiveness, these amphiphilic supramolecular assemblies can be used as a promising class of carriers to deliver varieties of therapeutic agents to targeted tumor sites for cancer therapy.

3.2. Biodegradability and Biocompatibility

Figure 6. Classes of aqueous compatible supramolecular polymers: A) water-soluble supramolecular polymers and B) amphiphilic supramolecular assemblies.

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The long-term accumulation of non-biodegradable or nonmetabolizable external vehicles is highly detrimental to the human body, and thus excellent biodegradability and biocompatibility are of great importance for the design and development of new physiologically friendly biomedical vehicles. In sharp contrast to conventional polymers, supramolecular polymers, which can be spontaneously degraded or metabolized in the variable physiological environment of the human body as a result of their dynamic/reversible non-covalent connections in the polymer backbone, display more prominent biodegradability and biocompatibility. Therefore, supramolecular polymers

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3.3. Stimuli-Responsiveness The clinical therapeutic effect of drug delivery or gene therapy is highly dependent on the release behavior of the delivery carriers in the human body. The stimuli-responsiveness is expected to regulate the release behavior of the delivery systems, thereby leading to a significant enhancement of in vitro and in vivo therapeutic efficacy. Therefore, stimuli-responsive polymers that have the ability to alter their structure and morphology to achieve controlled-release behavior upon exposure to a suitable external stimulus, have attracted much attention in wide range of biomedical fields. In order to realize a rapid and efficient release of therapeutic agents at tumor sites, a large number of stimuli-responsive covalent polymers have been widely used as smart biomedical vehicles, which can respond to various external stimuli such as pH, temperature, light, voltage, magnetic, redox, enzyme, etc.[131–134] However, these covalent polymers cannot withstand multiple responsive cycles, leading to an uncontrollable release behavior upon external stimuli, which can be attributed to the fact that covalent bonds in the polymer matrix are susceptible to damage but difficult to reversibly reform. Therefore, supramolecular chemistry provides an alternative strategy for the development of stimuli-responsive supramolecular polymers for diversified biomedical applications. Conceptually, the reversible nature of non-covalent interactions imparts the resulting supramolecular polymers with the capacity to undergo repeated reversible changes, to allow programmable and controlled delivery behavior. In this section, we

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with defined structure, controlled degradation profiles, and excellent biocompatibility, have great potential as a candidate for in vivo drug/gene/protein delivery systems, bioimaging agents, scaffolds for tissue engineering, and biomimetic materials. Hitherto, supramolecular polymers with outstanding biodegradability and biocompatibility can be fabricated by self-organization of either natural biomolecules or versatile biocompatible synthetic building blocks. For the former, these natural biomolecules such as phospholipids, peptides, and carbohydrates are the basic components of lipids, proteins and polysaccharides in nature; therefore, the supramolecular polymers constructed from these natural units are inherently biodegradable and biocompatible.[122,123] In contrast, the latter supramolecular polymers can be acquired by self-assembly of either synthetic small molecules or biodegradable and biocompatible synthetic polymers. Among them, these small-molecule-based supramolecular polymers are capable of being completely degraded into small-molecule species under variable physiological conditions owing to their small-molecule building blocks and non-covalent polymer backbone.[11,41,124–127] In addition, a large number of biodegradable, biocompatible or bioresorbable synthetic polymers, such as polyols, polyethers, polyesters, polylactides, and polyphosphates, have been widely used as ideal building blocks to prepare functional supramolecular polymers for cancer diagnosis and therapy.[110,128–130] With the readily available feedstocks and newly emerging synthetic technologies, more and more biodegradable and biocompatible supramolecular polymers will be designed and developed for diverse biomedical applications.

mainly focus on several typical stimuli-responsive supramolecular polymers, which are only sensitive to various physiological stimuli in human cells, tissues and organs such as pH, redox agents, enzyme, etc. As we know, extracellular pH in most tumor tissues is around 6.8, which is slightly more acidic than that in normal tissues (pH ≈ 7.4). In particular, the pH value in the endosome or the lysosome of cells can even reach around 5.0, thereby allowing pH-triggered drug release from the endocytosed nanocarriers.[135] Therefore, pH-responsive biomedical delivery systems that can rapidly respond to mildly acidic conditions provide an available platform for the achievement of controlled drug delivery in acidic tumor tissues. Because of their highly directional selection and fully reversible nature, multiple hydrogen-bonding interactions have been widely used to create pH-responsive supramolecular polymers.[5] The resultant hydrogen-bonded supramolecular polymeric systems show a sensitive response to the mildly acidic pH in tumor sites, and are capable of rapidly releasing loaded antitumor drugs at the tumor sites, resulting in a remarkably enhanced anti-tumor efficacy.[136] In addition, several types of host–guest supramolecular polymers also exhibit unique pH-responsive properties along with switchable structure and function, which holds great potential in the field of controlled drug delivery.[36,137,138] In the cytosol, the concentration of glutathione (GSH) usually reaches around 10 mM; particularly, the concentration of cytosolic GSH in certain tumor cells is found to be several times higher than that in normal cells.[139] Meanwhile, some tumor cells also show enhanced intrinsic oxidative stress resulting from large amounts of intracellular reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), superoxide anions, and hydroxyl radicals. It is worth noting that tumor cells exhibit an elevated level of H2O2 up to 0.5 nmol (104 cells)−1 h−1 compared with normal cells.[140] The reducing cytosol and oxidizing intracellular milieu in tumor tissues offer a great opportunity to fulfill redox-triggered intracellular delivery. Thus, redox-responsive supramolecular polymers can be used as smart carriers for controllable drug/gene/protein delivery in tumor tissues.[127,141,142] Currently, the β-CD/ferrocene host–guest couple with its unique redox-responsiveness has been intensively used to construct versatile redox-responsive supramolecular polymeric systems such as smart supramolecular drug/gene delivery carriers,[127] self-healing supramolecular hydrogels,[141] etc. Enzyme overexpression in the human body eventually leads to serious disease or even death, and thus a large amount of enzymes is usually found in elevated concentrations in various types of tumor cells or tissues. In recent years, enzyme-responsive supramolecular polymers[126,133,143–147] with good biocompatibility and a high degree of selectivity, have been widely used as promising carriers for delivering therapeutic agents to tumor sites for targeted, site-specific cancer therapy. As an example, Liu et al. reported an enzyme-responsive supramolecular vesicle by the aqueous self-assembly of a superamphiphile based on the host–guest interaction between a p-sulfonatocalix[4]-arene (SC4A) host (1) and a natural enzyme-cleavable myristoylcholine guest (2) (Figure 7A,B).[147] The obtained supramolecular binary vesicle displays highly specific and efficient responsiveness to cholinesterase, thereby leading to the disassembly of

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3.4. Targeting Chemotherapy usually leads to the death or apoptosis of both normal cells and cancer cells. Despite persistent and intense efforts to discover highly effective oncology drugs, a significant challenge that most therapeutic agents still face is their inability to be delivered effectively. In order to safely and efficiently deliver pharmaceutical agents to the required tumor tissues, the biomedical vehicles are required to have smart tumortargeting ability, which is capable of making pharmaceuticals accumulate non-specifically or specifically in pathological sites, to a considerable extent, resulting in the decreased lethality of normal cells and the improvement of delivery efficacy. In recent years, supramolecular chemistry offers a robust platform for the design and development of novel delivery systems to allow for the safe, high-dose, specific delivery of pharmaceutical agents to targeted tumor tissues. Generally, targeting of biomedical vehicles to tumor cells or tissues assumes two distinct strategies: passive and active targeting. Passive targeting refers to the size-dependent non-specific accumulation behavior of nanovehicles at tumor sites, whereas active targeting refers to the specific recognition and high-affinity binding of funcFigure 7. A) The self-assembly process of a superamphiphile formed by host–guest complexa- tional carriers to tumor cells. The detailed tion of SC4A (1) with myristoylcholine (2). B) High-resolution TEM image of supramolecular discussions are presented as follows. vesicular assemblies. C) Release behavior of HPTS loaded in supramolecular vesicles with or Rapidly proliferating tumor tissues display without BChE. Reproduced with permission.[147] Copyright 2012, American Chemical Society. fenestrated vasculature and poor lymphatic drainage, further leading to the enhanced permeability and retention effect (EPR) effect, which allows the vesicle and concomitant release of any hydrophilic guest nanocarriers to accumulate non-specifically at tumor sites, as molecules (e.g., the trisodium salt of 8-hydroxypyrene-1,3,6shown in Figure 8.[150] This is often referred to as passive tartrisulfonic acid (HPTS)) entrapped within the vesicular interior in response to butyrylcholinesterase (BChE) (Figure 7C). Theregeting, which is highly dependent on the size of nanovehicles fore, this enzyme-triggered supramolecular system holds great because of abundant intercellular spaces in tumor tissues. As potential for controlled delivering of Alzheimer's disease drugs a novel class of dynamic and non-covalent nanoassemblies, to specific enzyme sites in vivo. supramolecular polymers show typical size-dependent passive targeting to tumor tissues by the EPR effect. From a structural In addition, other types of stimuli-responsive supramolecperspective, the size and shape of supramolecular polymers ular polymers, to some extent, show modest potential as poscan be effectively regulated under exposure to certain environsible vehicles for biomedical applications. For example, light, mental stimuli benefiting from their dynamically switchable as a clean, highly efficient external source of stimulation, structures and highly sensitive stimuli-responsiveness. Furcan be readily switched from outside the system without thermore, the variation in size and shape of supramolecular any additional reagents. Compared with UV light, near polymers exerts a remarkable effect on their accumulation, infrared (NIR) light exhibits weaker scattering and larger adhesion and uptake behaviors in tumor tissues.[151,152] In addidepth of penetration into organisms, and thus NIR lightresponsiveness is expected to provide a robust platform for tion, other architectural features of supramolecular polymers the design of smart drug-delivery systems for programmable that inhibit the passage of a supramolecular polymer through and controlled drug delivery in the future.[148] In contrast to a pore of the kidney, such as higher molecular weight, lower chain flexibility, and higher degree of branching, help to avoid the aforementioned single stimuli-responsive ones, multielimination of the supramolecular polymers by the kidney, and stimuli-responsive supramolecular polymers can rapidly thus improve blood circulation time and tumor accumulation, respond to multiple external stimuli, but also are capable of further enhancing therapeutic efficacy.[150] adapting to complicated physiological environment in vivo, thereby showing great potential in clinical diagnosis and However, one major limitation of passive targeting is that treatment.[104,108,149] it is difficult to achieve a sufficiently high pharmaceutical

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concentration at the tumor site, leading to low therapeutic efficacy and serious adverse effects. To further improve the tumor specificity and therapeutic efficacy, a special focus has been put on exploiting supramolecular nanovehicles with active targeting ability. As depicted in Figure 9, the increased molecular mobility of targeting ligands provided by using the polyrotaxane backbone has been sown to be effective for enhancing active targeting to the corresponding cell-surface receptor proteins, which greatly shortened the response time of cell–material interactions.[153] In general, this class of active -targeting supramolecular polymers can be fabricated through supramolecular self-organization of bioactive functional molecules including peptides, proteins and carbohydrates.[122,123] The resulting functional

supramolecular nanostructures have the ability to proactively identify specific cell-surface receptors via specific molecular recognition between ligands and receptors. Owing to their modular architectures, tunable properties and facile functionalization, supramolecular polymers can also be readily modified or functionalized with varied targeting ligands in a non-covalent manner, such as folic acid, hyaluronic acid, Arg-Gly-Asp oligopeptides (RGD), antibodies, lectins, saccharides, and so forth, thereby achieving their active targeting.[153–156] This noncovalent modification or functionalization strategy of supramolecular polymers that does not require any additional chemical reactions, not only greatly reduces the preparation cost, but also effectively maintains the biological activity of targeting ligands.

Figure 9. Schematic illustration of enhanced active targeting via cooperative binding of RGD ligands on a dynamic polyrotaxane to target cell-surface receptors. Reproduced with permission.[153] Copyright 2013, American Chemical Society.

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domain to form a functional nanofibrous scaffold reminiscent of extracellular matrix for potential biomineralization applications (Figure 10A). By decreasing the pH below 4, this peptide amphiphile rapidly generated free-standing birefringent gels in water consisting of a fiber network (Figure 10B). After crosslinking, these fibers were capable of directing mineralization of hydroxyapatite to form mineralized nanofibers with plateshaped polycrystalline mineral (Figure 10C). Furthermore, these nanofibers from peptide amphiphiles had been used as promising materials for applications in several applications in the biomedical field, such as cell culture,[160] cell signaling,[161] and enzyme mimetics.[162] Recently, natural or artificial β-sheet peptides have been widely utilized as functional building blocks to prepare bioactive supramolecular polymers because of their biocompatible amino acid components, as Figure 10. A) Chemical structure of a peptide amphiphile (3) and schematic illustration of the well as the unique secondary structural features of the β-sheet structure along with the self-assembly of 3 into a nanofiber. B) Vitreous ice cryo-TEM of the nanofibers in their native α-helix.[164,165] To date, researchers have utihydrated state. C) TEM image of the unstained, crosslinked peptide nanofibers incubated in the aqueous solution of CaCl2 and Na2HPO4 for 30 min. The red arrows indicate that mature lized β-sheet-peptide-containing building peptide amphiphile crystals completely cover the resulting nanofibers. Reproduced with perblocks to create numerous bioactive supramission.[158] Copyright 2001, American Association for the Advancement of Science. molecular nanostructures for bioapplications, such as cell-penetrating peptide-coated nanoribbons for intracellular nanocar3.5. Bioactivity riers,[166] filament-shaped artificial viruses for simultaneously In nature, there is a diverse range of well-ordered functional delivering both small interfering RNA (siRNA) and encapsunanostructures at the cellular and sub-cellular level resulting lated hydrophobic guest molecules,[167] protein amyloid fibrils from the self-assembly of disordered biomolecular units,[157] for biotechnological applications,[168] etc. Moreover, the dynamic which has inspired the appearance of artificial supramolecular protein assembly along columnar supramolecular polymers has systems with analogous biological activity. This class of bioacbeen achieved through the site-specific covalent attachment of tive supramolecular polymers can be fabricated by the nondistinct SNAP-tag fusion proteins to self-aggregated benzylguacovalent self-organization of bioactive functional molecules nine decorated discotics.[169] including peptides, proteins, and carbohydrates, which have In biological systems, living things always interact with each been widely used as promising biomaterials for diverse bioother for signal communication and specific recognition. As medical applications. The supramolecular self-assembly of one of the most important bioactive functional components, bioactive building blocks offers several advantages such as the carbohydrates often play a key role in a large variety of basic responsive feature of the supramolecular architectures, the biological phenomena through carbohydrate-mediated multiease of non-covalent synthesis and the probability of incorpovalent interactions.[170–172] Commonly, carbohydrate-mediated rating a multiple array of different functional molecules. This multivalent interactions have been exploited using covalent section aims to highlight recent advances in the design and polymers as scaffolds for carbohydrate attachment.[173] In sharp synthesis of bioactive supramolecular polymers, with a special contrast, supramolecular assemblies have begun to emerge focus on their structure, bioactivity, and potential biomedical as alternative scaffolds for multivalent carbohydrate recogniapplications. tion,[174] showing tight and specific binding to host cells. A Peptides and proteins with unique biological activities play a recent series of studies has demonstrated the clear dependdecisive role in metabolic regulation and modulation. Peptideence of carbohydrate-mediated multivalent interactions on based or protein-based amphiphiles that consist of hydrophilic the size and morphology of supramolecular nanostructures. peptide or protein segments covalently bonded to different For example, the group of Lee has developed a library of biohydrophobic segments have been extensively used in the develactive supramolecular nanostructures by the self-assembly of opment of bioactive supramolecular polymers due to their mannose-functionalized aromatic rod-coil amphiphiles (4–6) versatile structures and excellent biocompatibility.[158–163] As a (Figure 11A).[175,176] By systematically adjusting the relative typical example, Stupp and co-workers[158,159] reported the selfvolume fraction between the hydrophilic and hydrophobic segments of the amphiphiles, the size and shape of the supramoorganization of peptide amphiphiles (3) involving a hydrophilic lecular nanostructures can be readily controlled, ranging from functional peptide domain and a hydrophobic self-assembly

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can be reversibly switched under exposure to certain external stimuli. Furthermore, these specific functions afford supramolecular polymers with great potential for a wide range of biological applications. In this section, we briefly summarize the most remarkable advances in optical supramolecular polymers, electronic supramolecular polymers, and self-healing supramolecular polymers (Figure 12) concerning three correlative aspects of crucial importance: structure, functionality, and potential application. As an excellent candidate for application in bioimaging, biosensing, and diagnosis, π-conjugated polymers with typical photoluminescence behaviors have gained significant attention in the past decade.[183,184] The desirable optical functionality of these π-conjugated polymers is greatly dependent on their intrinsic molecular structure, as well as on intermolecular interactions in the aggregated states. However, conventional π-conjugated polymers have certain inherent Figure 11. A) Molecular structures of 4–6, as well as schematic representation of vesicles, disadvantages, including complicated purifimicelles, and nanofibers assembled from 4, 5, and 6, respectively. B) TEM images of various cation process, unavoidable structural defects assemblies. Reproduced with permission.[176] Copyright 2005, American Chemical Society. and low solubility, which exert a dominant negative effect on the resulting optical functionality of biodetection devices. Alternatively, the programmed micelles to vesicles and nanofibers (Figure 11B). The resulting supramolecular organization of optical components that effeccarbohydrate-coated supramolecular systems can serve as effectively overcomes these obstacles opens a new avenue to the tive multivalent ligands for lectin concanavalin A (Con A) and creation of novel bioimaging probes and smart supramolecular Escherichia coli bacteria, which shows much higher inhibitory devices, since small molecules are accessible in high purity, and potency compared with α-D-methyl mannose. Moreover, the their supramolecular polymerization can be accomplished in a addition of a hydrophobic guest molecule (e.g., Nile red)[177] reversible and predictable manner. Currently, a large number or an amphiphile with a different crystallinity[178] further leads to a remarkable variation in the size and morphology of carbohydrate-coated supramolecular nanostructures, thereby providing a novel strategy to control the biological activities of supramolecular polymers. Additionally, other types of carbohydrate-coated supramolecular systems have also been exploited such as multifunctional fluorescent nanoparticles[179,180] and supramolecular polyrotaxanes.[181,182] In particular, maltosefunctionalized supramolecular polyrotaxanes displayed greatly enhanced multivalent interaction with protein receptor binding sites due to the high mobility of the ligands in polyrotaxanes, thus leading to much stronger inhibitory effects on lectin Con A than maltose itself.[181]

3.6. Functionality Apart from the several basic physicochemical properties given above, supramolecular polymers also display specific functions such as optical, electronic, and self-healing functionalities. The optical and electronic functionalities mainly derive from the intrinsic molecular structures of π-conjugated building blocks, whereas the self-healing functionality is highly dependent on the non-covalent connections in the polymer backbone. Owing to their non-covalent polymer backbones and smart stimuliresponsiveness, these functional supramolecular polymers

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Figure 12. Schematic illustration of: A) optical supramolecular polymers, B) electronic supramolecular polymers, and C) self-healing supramolecular polymers.

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of fluorescent supramolecular polymers (Figure 12A) have been widely fabricated by using diverse types of non-covalent interactions involving metal–ligand coordination,[185,186] multiple hydrogen bonding,[187–192] and host–guest interactions.[193–196] The resulting fluorescent supramolecular polymers hold the ability to rapidly respond to variable biological stimuli, showing great potential as biological probes for in vitro or in vivo bioimaging and biodetection. In comparison, phosphorescent supramolecular polymers have several unique advantages such as low-cost solution processing and their theoretical 100% internal quantum efficiency,[197–201] and they can be used as promising light-emitting materials in miniature sensors and bioimaging probes in near future. Recently, supramolecular electronics[202] has been proposed as a promising intermediary-scale strategy to construct welldefined electronic supramolecular polymers from electronic components on the 5–100 nm length scale, ranging from molecular electronics (Å) to plastic electronics (µm). However, molecular electronics has problems arising from contact with the electrodes and from thermal noise, which produces undesired orientation and conformational motions,[203] whereas plastic electronics has limitations in the precise ordering of their ‘‘crystalline’’ domains, thus affecting the mobility of charge carriers required for enhanced performance.[204] Supramolecular self-assembly offers an efficient bottom-up strategy for positioning well-defined shape-persistent building blocks under thermodynamic control at predefined locations,[205,206] leading to the formation of the smallest dimensions with 100% ‘‘crystalline’’ organization in the resulting self-assembled structures. In the past decade, a great number of electronic supramolecular polymers (Figure 12B) with various forms[22,207–209] has been constructed through the molecular self-assembly of three major categories of building blocks, involving aromatic π-stacks, sulfur-containing π-electron systems, and lightresponsive triarylamine π-stacks. The electronic supramolecular polymers formed from planar aromatic π-stacks exhibit one-dimensional well-defined nanostructures and prominent conductive performances.[64,210–214] By delicately designing the molecular structures of the building blocks based on aromatic π-stacks, it is possible to improve the softness and processability of these materials while keeping their conductive properties. Additionally, sulfur-containing π-electron systems including (oligo)thiophenes and tetrathiafulvalenes have been extensively utilized to build a rich collection of electronic supramolecular nanostructures,[215,216] which have great potential for use as promising materials for organic electronics and thin-film optoelectronic devices. Light-responsive triarylamine π-stacks possessing interesting photoconductivity properties and high hole-transport mobility, show great potential as active materials for application in optoelectronic devices.[217,218] Due to the automatic healing nature and their wide applications in many fields, self-healing polymers that have the ability to spontaneously/autonomously repair their damage and recover their performance upon exposure to a suitable external stimulus have attracted much attention recently. In view of the synthesis strategies, self-healing polymers can be divided into two major types, including self-healing covalent polymers[219–221] and self-healing supramolecular polymers.[222–224] However, covalent polymers cannot withstand multiple healing cycles,

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leading to a substantial loss of performance during this process, which can be attributed to the fact that the covalent bonds in the polymer matrix are susceptible to damage, and are difficult to restore to their initial state. Therefore, supramolecular chemistry offers an alternative approach for the development of self-healing supramolecular polymers by using reversible non-covalent interactions. Conceptually, the reversible nature of non-covalent interactions imparts the resulting supramolecular polymers with the capacity to achieve repeated healing at the molecular level to fully restore the original polymer properties.[225] Hitherto, various non-covalent interactions, such as multiple hydrogen bonding,[226–229] π−π stacking,[230–232] metal– ligand coordination[233–235] and host–guest interactions,[141] have been widely employed to generate numerous self-healing supramolecular polymers (Figure 12C), some of which could be used as stimuli-responsive drug-delivery carriers and peripheral vascular embolization materials.

4. Biomedical Applications As mentioned above, functional supramolecular polymers not only display specific properties and functions, but also have the ability to undergo reversible switching of structure, shape, and function in response to certain external stimuli, making them outstanding candidates for a wide range of biomedical applications. In this section, we focus on the application of functional supramolecular polymers in for applications in the biomedical field, including drug delivery, gene transfection, protein delivery, bioimaging and diagnosis, tissue engineering, and biomimetic chemistry.

4.1. Drug Delivery Drug delivery refers to technologies, formulations, approaches, and systems for delivering pharmaceutical agents into human tumor tissues to safely realize its expected therapeutic effect.[236,237] Up to now, a large number of supramolecular systems have been widely used as promising drug carriers for improving the water-solubility and bioavailability of drugs, inducing preferential accumulation at tumor sites through the EPR effect, prolonging the circulation time, and reducing systemic side effects.[238–240] In sharp contrast to conventional polymeric carriers,[241–244] supramolecular drug carriers have the capability to undergo rapid changes in response to certain external stimulus (e.g., pH, temperature, light, oxidizing or reducing agent, enzyme, etc.), thereby enabling the controllable release of encapsulated drugs into the media. Currently, supramolecular drug-delivery systems mainly contain supramolecular drug complexes, hydrogen-bonded supramolecular polymeric systems, and host–guest supramolecular polymeric systems, and display unique advantages in drug delivery. In this section, we focus on the current progress in supramolecular polymeric systems for drug delivery. Hydrogen-bonded supramolecular polymers are highly sensitive to environmental pH variation, making them fascinating candidates for pH-triggered anti-cancer and antiinflammatory drug delivery because of the acidic tumor sites

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and inflammatory tissues. As an example, Dankers and coworkers[245] presented the development of supramolecular hydrogels for in vivo intrarenal drug delivery. They synthesized two different classes of supramolecular UPy-modified hydrogelators through linking the UPy units to poly(ethylene glycol) (PEG) chains by two distinct methods: chain-extended hydrogelators containing UPy moieties in the backbone (7 and 8) and bifunctional hydrogelators end-functionalized with UPy units (9) (Figure 13A). The chain-extended materials formed strong, shape-persistent hydrogels (Gel-7 and Gel-8), while the bifunctional material formed a weaker, elastic hydrogel (Gel-9) (Figure 13B). The resulting supramolecular hydrogels displayed distinct tissue responses, owing to their different physicochemical properties. In comparison, the bifunctional hydrogel (Gel9) ultimately exhibited the lowest tissue response of all three hydrogels 15 days after implantation (Figure 13C). Therefore, the soft, weaker, and fast-eroding bifunctional hydrogels were notably suitable for short-term, fast delivery of drugs to the kidney cortex, while the flexible, strong, and slowly eroding chain-extended hydrogels were found to be suitable for longterm intrarenal delivery of organic drugs. This class of supramolecular hydrogels with its favorable biological behavior can be used as exquisite carriers for subcapsular drug delivery, and opens up a new way for intrarenal therapy. In addition, we prepared a series of amphiphilic supramolecular copolymers based on multiple hydrogen-bonding recognition of nucleobases, which could self-assemble into pH-responsive spherical micelles in water as promising carriers to achieve controlled

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Figure 13. A) Chemical structures of the UPy modified hydrogelators including chain-extended UPy-modified hydrogelators (7 and 8) and end-functionalized UPy-hydrogelator (9). B) Schematic representation of the proposed degradation behavior for these supramolecular hydrogels. C) Tissue slices were stained for the macrophage marker ED1 after 15 days of implantation. Reproduced with permission.[245] Copyright 2012, Elsevier.

drug release in vitro.[136,246] Compared with conventional covalent polymeric carriers, these supramolecular polymeric carriers displayed much faster release rate while arriving at the pathological sites, thereby resulting in enhancing the therapeutic efficacy as well as reducing drug resistance. In recent years, a large number of peptide-containing selfdelivery supramolecular nanostructures, including supramolecular micelles, supramolecular biomembranes, and supramolecular hydrogels have been widely developed by aqueous self-assembly of amphiphilic peptide derivatives. In one study, Tirrell et al. reported a class of supramolecular cylindrical micelles self-assembled from a peptide amphiphile consisting of a hydrophilic model cytotoxic T-cell epitope and a hydrophobic synthetic lipid tail.[247] The resulting supramolecular micelles were capable of inducing a cytotoxic T-cell response in mice, which effectively inhibited the growth of tumors expressing the tumor antigen. Also, Stupp and co-workers[248] fabricated robust, ordered hybrid supramolecular membranes by the self-assembly of hyaluronic acid with positively charged peptide-based architectures containing anti-tumor peptide amphiphiles with a (KLAKLAK)2 peptide sequence. The resulting supramolecular biomembranes could serve as a reservoir for controlled release of cytotoxicity upon enzymatic degradation or as a material with highly localized surface cytotoxicity. This study provides a potential approach to design drugdelivery systems for anti-tumor therapeutics. Moreover, the group of Xu[249–251] has reported a series of peptide-containing self-delivery supramolecular hydrogels synthesized by aqueous self-assembly of the peptide derivatives, which undergo a gelto-sol transition caused by reduction, resulting in the efficient release of anti-inflammatory agent or anti-HIV prodrugs. This study offers a revolutionary approach for designing functional supramolecular biomaterials for site-specific drug delivery. CDs and their derivatives have been extensively used to build various host–guest supramolecular nanostructures with different sizes and morphologies, as well as to engineer functional supramolecular materials for drug delivery owing to their low cytotoxicity and weak immunogenicity.[252] For example, CDs have been successfully employed to form inclusion complexes with hydrophobic drugs via host–guest interactions in pharmaceutical fields, such as alleviating local and systemic toxicity,[238] increasing drug solubility and stability,[253] enhancing drug absorption,[254] and controlling drug-release profiles,[255] as well as improving drug permeability across biological barriers.[256] Recently, the group of Li[130,257,258] reported a broad spectrum of CD-based supramolecular drug-delivery systems including supramolecular hydrogels, CD-drug complexes and supramolecular nanoparticles. They fabricated a novel type of supramolecular hydrogels through the host–guest complexation of α-CD and a biodegradable PEG-poly[(R)-3-hydroxybutyrate]PEG triblock copolymer, which has a thixotropic and reversible nature, and thereby could be applied for relatively long-term sustained delivery of macromolecular drugs as an injectable formulation.[130] Subsequently, by combining host–guest interactions for chemotherapeutic drug loading with electrostatic interaction for DNA condensation, they further developed different multifunctional supramolecular co-delivery systems to achieve the cooperative co-delivery of chemotherapeutic anticancer drug and plasmid DNA in vitro and in vivo.[257,258] In

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addition, our research group and others also have reported a variety of CD-based supramolecular drug-delivery systems in recent years.[259–261] Apart from CDs, other supramolecular hosts, such as calix[n]arene, cucurbit[n]uril and pillar[n]arene, can also be utilized to design promising supramolecular drug carriers for drug delivery. As an example, we reported a calix[4]arene-based supramolecular drug-delivery system used for efficient photodynamic therapy.[262] In this system, an amphiphilic supramolecular polymer was constructed through the host–guest interaction between hydrophilic PEGylated calix[4]arene (10) and hydrophobic photosensitizer chlorine e6 (Ce6) (11), which could assemble into supramolecular polymeric micelles with an average diameter of 95.6 nm (Figure 14A). Without photoirradiation, the resultant Ce6-loaded supramolecular micelles with a drug loading content of 12% displayed low cytotoxicity in HeLa cells, and could thus be used as a safe drug-delivery carrier. The formation of micelles effectively shielded the negative charges of Ce6, facilitating their cellular uptake by HeLa cells. Furthermore, these supramolecular micelles exhibited

more efficient in vitro photodynamic therapy efficacy than free Ce6 (Figure 14B). This work provides a novel approach for the preparation of supramolecular drug-delivery systems for photodynamic therapy. Also, we further prepared a new type of porphyrin-based supramolecular nanoparticles by self-assembly of a supramolecular porphyrin amphiphile, which showed dynamic/reversible variations in morphology and optical properties in response to light. It is expected that this type of porphyrin-based spherical nanoparticle can be used in vitro as a potential photosensitizing agent for photodynamic therapy.[263] Similarly, Zhang and co-workers[264] fabricated a novel supramolecular photosensitizer via an intense host–guest interaction between cucurbit[7]uril and a naphthalene-modified porphyrin, which showed a remarkably improved anti-bacterial efficiency. Very recently, various stimuli-responsive (e.g., pH, glutathione, and cholinesterase) supramolecular polymeric vesicles have been prepared as smart vehicles for application in controlled drug delivery.[138,147,265] Moreover, gold-containing supramolecular polymeric systems have also been successfully applied for the treatment of cancer cells because of their enhanced photothermal effects.[266,267]

4.2. Gene Transfection

Figure 14. A) Chemical structures of star-shaped calix[4]arene (10), chlorine e6 (Ce6) (11) and a schematic illustration of the preparation of supramolecular polymeric micelles via the host–guest interaction. B) In vitro cytotoxicity of DC4-PEG/Ce6 micelles (䉭) and free Ce6 (䊉) with photoirradiation. Reproduced with permission.[262] Copyright 2011, Royal Society of Chemistry.

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Gene therapy, using nonviral vector systems such as cationic lipids, polymers, dendrimers, and peptides, has gained enormous attention during the past two decades as a potential approach for correcting genetic disorders and an alternative strategy to conventional chemotherapy used in treating countless diseases.[268–270] Currently, research efforts are mainly focused on designing effective and less-toxic cationic vectors that are capable of compacting DNA and avoiding cellular barriers for safe and efficient gene delivery. The majority of nonviral vectors used in gene therapy are, typically, covalent polycations,[271–274] which have several fundamental problems, including tedious synthesis, complicated purification process, and lack of responsiveness. As an alternative approach, supramolecular chemistry provides a robust platform for the preparation of cationic supramolecular polymers with dynamic structures and tunable performance, which can be used as promising vectors for gene delivery. A series of supramolecular polycations based on non-covalent interactions has been successfully designed and developed for gene transfer, and shows excellent transfection efficiency compared with covalent ones. This section briefly discusses the recent advances and future challenges in the field of supramolecular-polymer-based gene therapy. As a class of mechanically interlocked supramolecular polymers, polyrotaxanes, which are composed of many cyclic molecules threaded by an axial polymer, have been demonstrated as a perfect candidate for molecular machines and stimuliresponsive nanosystems. Typically, the cyclic molecules in polyrotaxanes can slide and rotate freely along their axis, eventually endowing this supramolecular system with unusual features including “mobile” ligands and multivalent interactions. In particular, CD-based polyrotaxanes, which have excellent biodegradation and biocompatibility as well as facile functionalization, have been widely used as promising carriers for

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applications in the biomedical field.[109,275,276] Kissel et al.[277] presented the first example in which rotaxanation of a cationic block copolymer with α-CDs led to the enhancement of genedelivery efficacy. Yui and co-workers[278,279] designed a cytocleavable cationic polyrotaxane with a necklace-like structure composed of a lot of dimethylaminoethyl-modified α-CDs and a disulfide-terminated PEG chain (Mn = 4 kDa). This polyrotaxane showed efficient cleavage of disulfide linkages under reducible condition, leading to rapid endosomal escape and improved gene delivery to the nucleus. In parallel, Li et al.[280] reported a series of cationic supramolecular polyrotaxanes consisting of multiple oligoethylenimine-grafted β-CDs threaded on a PEG-poly(propylene glycol)-PEG (PEG-PPG-PEG) triblock copolymer. In their design, the higher stability of PPG/β-CD compared with PEG/β-CD complexes remarkably limited the number of β-CD units threaded on this ternary copolymer, offering enough space for β-CD units to slide freely along the polymer, and thereby facilitated optimal electrostatic interaction between the oligoethylenimine (OEI) and the pDNA. This class of cationic supramolecular vectors showed excellent DNA condensation capability, low cytotoxicity, and high gene-transfection efficiency comparable to that of branched polyethylenimine (PEI) (25 kDa). Differently, Amiel and co-workers[281–283] exploited a novel type of supramolecular gene vector resulting from the association between a neutral crosslinked CD polymer and cationic adamantyl derivatives based on the CD/AD host–guest interaction. The charge density of the supramolecular polycations could be effectively controlled by changing the proportion of cationic guest molecules, thereby providing the possibility of regulating their DNA condensation capabilities. The gene-transfection efficiency of the resulting ternary DNA complexes is significantly dependent on the charge density of the supramolecular vectors. The best-performing formulation associated with

the use of a fusiogenic component exhibited a greatly improved transfection efficiency comparable with that of DOTAP-based lipoplexes.[283] Interestingly, the resulting CD-based spherical polyplexes formed by the electrostatic complexation of cationic supramolecular polymers and DNA could be non-covalently modified at their surface by employing their intrinsic inclusion capabilities. By taking advantage of this property, Davis and coworkers further endowed the resulting DNA nanoparticles with stability and targeting capabilities by incorporation of diverse functional components, such as AD-modified PEG (AD-PEG), which prevented aggregation and non-specific interactions with biological components,[284] galactosylated AD-PEG, which imparted selectivity towards hepatocytes with galactose specific membrane receptors,[285] and transferrin-modified AD-PEG, which enhanced the targeting ability to K562 cells[286,287] or human tumors.[288] Very recently, we have exploited a facile supramolecular approach to fabricate charge-tunable cationic dendritic polymers through the β-CD/AD host–guest interaction between an AD-modified hyperbranched polyglycerol (HPG) (12) and primary-amine- or tertiary-amine-modified β-CD derivatives (13, 14) (Figure 15A).[289] This supramolecular system perfectly combines the multifunctionality of dendritic polymers and the dynamic/tunable capability of supramolecular polymers. As a result, the surface charge and molecular functionality of these polycations can be readily optimized through tuning the ratio of these two cationic β-CD derivatives. The results demonstrate that both DNA condensation capability and buffer capacity of these supramolecular polycations are greatly enhanced by increasing the proportion of tertiary amine-modified β-CDs. Finally, the optimized supramolecular gene vectors show superior transfection efficiency in COS-7 cells, which is comparable with or even slightly higher than that of branched PEI (25 kDa) (Figure 15B).

Figure 15. A) Preparation of charge-tunable cationic supramolecular dendritic polymers via the β-CD/AD host–guest interaction between HPG-AD (12) and different cationic β-CD derivatives (13, 14). B) Luciferase expression (top panel) and GFP expression (bottom panel) of these cationic supramolecular polymers in COS-7 cells. Reproduced with permission.[289] Copyright 2011, Royal Society of Chemistry.

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Hitherto, almost all supramolecular polymeric vectors for gene therapy have been prepared via host–guest recognition between high-molecular-weight polymers and low-molecularweight cationic derivatives. In other words, a high-molecularweight polymer is the indispensable building unit of current supramolecular polymeric vectors. To our knowledge, cationic supramolecular polymers constructed completely from smallmolecule building blocks have not yet been used for biomedical applications, which can be attributed to the fact that these supramolecular polymers are highly susceptible to depolymerization under exposure to external stimuli. To this end, we reported the first example of small-molecule-based supramolecular polycations as a promising nonviral vector for gene delivery.[127] This class of cationic supramolecular alternative polymers was constructed through the host–guest complexation between a ferrocene dimer (15) and a β-CD dimer (16) (Figure 16A), and it could undergo redox-triggered reversible polymerization and depolymerization on alternating addition of hydrogen peroxide (H2O2) and GSH. Importantly, this small-molecule-based supramolecular polymer had the ability to effectively condense DNA and rapidly release DNA triggered by H2O2 (Figure 16B). The luciferase expression assay was performed to evaluate the transfection efficiency of this redox-responsive supramolecular vector in different cell lines. The results demonstrated that this supramolecular polymer showed moderate gene transfection efficacy (around 106 RLU mg−1 protein) in COS-7 cells, but much lower transfection efficacy (ca. 103 RLU mg−1 protein) in cancer cells (e.g., HeLa cells and MCF-7 cells) (Figure 16C). The excess H2O2 in cancer cells triggered the faster and earlier DNA release from the dissociated DNA polyplexes, leading to a remarkable decrease of transfection efficacy in cancer cells. Further structural optimization of these small-molecule-based supramolecular vectors is required to achieve efficient and targeted gene delivery, e.g., the development of supramolecular polycations with high polymerization degree and high charge density, as well as the incorporation of cell-targeting ligands.

4.3. Protein Delivery Protein delivery, wherein proteins are delivered into a living system to replace dysfunctional proteins, has been regarded as the most safe and efficient method for curing diseases in recent years.[290,291] Nevertheless, the efficacy of protein-based biotherapeutics has been greatly restricted due to their poor stability against proteases and low delivery efficiency in both the digestive and circulatory systems. For example, these proteins are removed easily by proteolytic digestion and renal excretion.[292] A variety of protein-delivery systems has been successfully constructed to enhance protein stability and weaken immunogenicity. Benefiting from their controlled size and shape, as well as dynamically tunable properties, various supramolecular systems have been widely used as promising vehicles for protein delivery, including nanoparticles, nanocapsules, nanofibers, nanotubes, and hydrogels. This section mainly focuses on the current advances in the field of protein delivery using supramolecular carriers. Currently, a number of supramolecular hydrogels has been utilized as emerging carriers for encapsulation and release of

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Figure 16. A) Schematic illustration of a cationic supramolecular polymer (CSP) constructed via orthogonal host–guest interaction between Fc2 (15) and β-CD2 (16) as well as its H2O2-triggered pDNA release behavior. B) Agarose gel electrophoresis retardation of pDNA by supramolecular polymer before and after addition of H2O2. Luciferase expression of CSP/pDNA polyplexes with different N/P ratios and branched PEI/pDNA polyplexes at a N/P ratio of 10 after 48 h in (C1) COS-7 cells, (C2) HeLa cells and (C3) MCF-7 cells. Reproduced with permission.[127] Copyright 2013, Royal Society of Chemistry.

proteins. As a typical example, Scherman and co-workers[112] prepared a novel class of high-water-content (up to 99.5%) cellulose-based supramolecular hydrogels formed from naphthyl-functionalized cellulose derivative (17), viologen-modified poly(vinyl alcohol) polymer (18), and cucurbit[8]uril (CB[8]) (Figure 17A). These supramolecular hydrogels exhibited several advantages, such as facile processing, simple preparation, available renewable resources, and tunable mechanical properties, making them eminent candidates for a wide range of biomedical applications. Release studies of therapeutic proteins (e.g., lysozyme and bovine serum albumen) from supramolecular hydrogels were performed to evaluate the effect of both protein molecular weight and polymer loading of the supramolecular hydrogels on the protein release rate. An extremely sustainedrelease profile of bovine serum albumin was observed over the

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course of up to 160 days from supramolecular hydrogels containing a polymeric content of only only 1.5 wt% (Figure 17B). This prolonged sustained-release behavior far exceeded previously reported protein release from hydrogels, demonstrating these supramolecular hydrogels suitable for sustained therapeutic applications. Also, a photoresponsive hydrogel system that was constructed via the host–guest interaction between β-CD-modified dextran and azobenzene-carrying dextran, could be employed for a light-controlled protein-release system.[293] Upon UV light irradiation, trans-azobenzene moieties in this hydrogel were converted into the cis-form, resulting in the dissociation of the crosslinking network and the release of entrapped green fluorescent protein (GFP) into the media. In addition, Kameta and Shimizu[294,295] demonstrated the selfassembly of supramolecular nanotubes having an inner recognition probe on the interior surface, which could be used not only for detecting the encapsulation and release behavior of GFP in real time, but also for sensing the stability of GFP in the hollow cylinder. This work provided a facile strategy for

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Figure 17. A) Host–guest complexation of cucurbit[8]uril (CB[8]), naphthyl-functionalized cellulose derivative (17) and viologen-modified poly(vinyl alcohol) polymer (18) in water and schematic illustration of the formation of supramolecular hydrogels with extremely high water content via a specific host–guest interaction of CB[8]. B) Cumulative release of both BSA and lysozyme (0.5 wt%) from supramolecular hydrogels with different polymer loadings (1.5 wt% and 0.5 wt%). Reproduced with permission.[112] Copyright 2012, Elsevier.

tailoring supramolecular nanotubes with various functional units at a specific location. Furthermore, several supramolecular polymeric systems, such as nanoparticles and hydrogels, have been widely applied for protein delivery in vitro and in vivo. For example, Tseng et al.[296] used supramolecular nanoparticles as a class of nanoscale carriers to deliver intact transcription factor (TF) with efficient transduction efficiency. In order to facilitate the encapsulation of the model TF into the supramolecular nanoparticles, an anionic TF-DNA complex was firstly formed using a plasmid DNA with a matching recognition sequence specific to a TF, which was then entrapped into supramolecular vectors by electrostatic interaction (Figure 18A). To evaluate the delivery performance of TF-DNA/SNPs, they performed the cell uptake studies by incubating TF-DNA/SNPs with HeLa cells. In Figure 18B, Cy5-labeled TF-DNA/SNPs displayed remarkably enhanced delivery performance compared with other controlled samples. In particular, the delivery efficacy of TF-DNA/SNPs was approximately five times higher than that of TAT-TF as a standard method for TF delivery. Furthermore, they quantified the luciferase expression by measuring the bioluminescence intensity of TF-DNA/SNPs treated cells to confirm that the TF retained its activity after delivery (Figure 18C). In contrast to the control experiments, the bioluminescence intensity for TF-DNA/SNPs-treated HeLa cells was significantly higher, indicating that the TF retains its activity to trigger luciferase expression after intracellular delivery. In comparison, Meijer and co-workers[297] have presented a new series of transient supramolecular networks based on quadruple hydrogen-bonded supramolecular polymers, which exhibited a non-linear behavior in formation, erosion, and selfhealing, showing great potential as protein vehicles for in vivo protein delivery. These growth-factor-encapsulated supramolecular materials with thixotropic behavior could thereby be implanted under the kidney capsule of rats using a minimally invasive injection. It was difficult to observe the supramolecular materials macroscopically by the naked eye in the explanted kidneys after about seven days, revealing that these polymers had eroded and the growth factor proteins were delivered. This study provides a modular approach by which the macroscopic rheological behavior and materials properties can be switched by controllable microscopic kinetics of the non-covalent interactions. Very recently, Chamuleau and Dankers[298] developed a pH-responsive and self-healing supramolecular hydrogel for growth-factor delivery. This supramolecular hydrogel could be converted into liquid at pH > 8.5 with a viscosity low enough for it to pass through a long catheter, while rapidly forming a hydrogel in contact with tissues. Growth factors were released from the supramolecular hydrogel, thereby displaying a significant reduction of infarct scar in a pig myocardial infarction model. In addition, distinct types of functional supramolecular polymeric systems have also been exploited to achieve efficient delivery of proteins.[299–301]

4.4. Bioimaging and Diagnosis Bioimaging is an emerging research field aimed at using sophisticated bioimaging probes to visualize specific molecular

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Figure 18. A) Schematic illustration of the supramolecular approach for the fabrication of transcription factor-incorporated supramolecular nanoparticles (TF-DNA/SNPs). B) Delivery efficacy of Cy5-labeled TF-DNA/ SNPs, Cy5-labeled-TF alone (TF), Cy5-labeled-TF-DNA complex, and Cy5labeled-TF conjugated with TAT (TAT-TF). C) Bioluminescence imaging of TF-DNA/SNPs-treated HeLa cells along with the controlled experiments based on TF-DNA complex and DNA/SNPs. Reproduced with permission.[296] Copyright 2011, Wiley-VCH.

pathways in vivo; in particular, those that play a crucial role in disease processes.[302,303] Bioimaging benefits the integration of complicated biological phenomena into the rapid visualization process at the molecular level, which extends the applications into diagnosis, treatment as well as high-throughput drug screening. In the past few decades, many imaging techniques, such as fluorescent probes for optical imaging, paramagnetic agents for magnetic resonance imaging (MRI), radiolabeled probes for nuclear imaging, and acoustically active microbubbles for ultrasound imaging, have been extensively used in clinical diagnosis and treatment.[304,305] Currently, the majority of bioimaging probes utilized in clinical practice are smallmolecule compounds that tend to be unstable, toxic, nonspecific, and rapidly cleared. In sharp contrast, polymer-based bioimaging probes have remarkably improved stability, reduced toxicity, prolonged plasma half-lives, and enhanced target specificity, and can be used as promising candidates for specifically targeted clinical bioimaging in the future.[306–310] In particular, a combination of supramolecular chemistry and imaging science leads to the generation of supramolecular-polymer-based bioimaging probes for the diagnosis and treatment of diseases,

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showing several unique advantages, such as controlled structures, tunable properties, and facile functionalization compared with conventional polymeric bioimaging probes. In this section, we briefly describe the recent progress in supramolecular polymeric probes and highlight their potential applications in bioimaging. Optical imaging is the most widely used bioimaging technique in diagnosis, clinical studies, and treatment planning, because fluorescent probes are safe and sensitive, and can be specifically labeled to other components. The basic obstacles for optical imaging of biological systems are autofluorescence, light scattering, and absorption by tissues in the visible region.[311] Recently, a variety of supramolecular fluorescent probes such as molecular complexes,[312] linear supramolecular polymers[313] nanoparticles,[314–320] nanofibers,[321,322] and gels,[323] have been extensively exploited using different noncovalent strategies, thereby allowing for efficient in vitro or in vivo bioimaging. By using a “bricks and mortar” strategy, we prepared a new type of calcein-based supramolecular fluorescent nanoparticles by aqueous self-assembly of β-CD-grafted branched PEI (PEI-CD) (19), AD-functionalized calcein (CAAD) (20), AD-functionalized PEG derivative (mPEG-AD) (21), and AD-functionalized folate (FA-AD) (22) via β-CD/AD host– guest interaction (Figure 19A).[314] In this system, the β-CD/ AD host–guest interaction remarkably suppressed the fluorescence self-quenching of calcein fluorescent dyes caused by the π-π stacking, thus providing an effective approach to fabricate highly fluorescent nanomaterials. This supramolecular system offered several advantages including controllable nanoparticle size, outstanding fluorescent properties and smart tumor-specific targeting ability. By incorporation of the folate receptor, this class of supramolecular fluorescent nanoparticles exhibited enhanced bioimaging efficacy in HeLa cells owing to the folatemediated cancer targeting (Figure 19B). In addition, Wang and co-workers[315] reported a type of supramolecular nanoaggregates assembled from bis(pyrene) derivatives that displayed high pH-stability and photostability. These nanoaggregates could be employed as stable fluorescent probe for lysosome-targeted imaging in living cells with negligible cytotoxicity. They also achieved the on-chip preparation of size-controllable supramolecular gelatin nanoparticles with a quantum-dot (QD) payload as matrix-metalloproteinase-responsive tumor-cell-imaging probes.[316] Nowadays, the rational design of multifunctional supramolecular nanomaterials for both diagnostic and therapeutic purposes has become one of the most challenging and exciting topics in nanomedicine. In another example, Li et al.[317] constructed novel multifunctional supramolecular hybrid nanocarriers consisting of a red-fluorescence QD core and a β-CD-OEI star-like cationic polymer suitable for cooperative co-delivery of DNA and anti-cancer drug (paclitaxel), as well as simultaneous cellular imaging. The imaging function of this hybrid nanocarrier provided the self-tracking ability to allow the precise localization of the supramolecular co-delivery system in cells. Different from other bioimaging techniques, MRI is a safe and non-invasive bioimaging technique, which utilizes a magnetic field or radio waves to generate high-quality images of the organs and structures of the human body.[324,325] Due to the advantages of MRI, including high spatial resolution, a

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Gd3+-DTPA complexes. MRI was then used to monitor the dynamic lymphatic drainage of the Gd3+-DOTA nanoparticles after injecting a Gd3+-DOTA nanoparticle solution into the right footpad of mice. The signal increase of the brachial lymph node in T1-weighted imaging could be observed after injecting Gd3+DOTA nanoparticles rather than Gd3+-DTPA, revealing that the Gd3+-DOTA nanoparticles could act as a potential vehicle for cancer metastasis diagnosis. Very recently, Liu et al.[313] reported a linear supramolecular polymer constructed through the intermolecular inclusion complexation of bridged bis(permethylβ-CD) with MnIII-porphyrin bearing PEG side chains, showing considerably enhanced MR signal for in vitro and in vivo MRI. This work provides a new direction for supramolecular polymers in the bioimaging field. Additionally, supramolecular nuclear-imaging probes with high sensitivity have also been designed and developed. For example, Tseng and co-workers[319] exploited a flexible and robust synthetic strategy for fabricating size-controlled supramolecular nanoparticles. To explore the use of the supramolecular nanoparticles for immune modulation, microPET/CT imaging was performed to investigate lymph node trafficking by injecting 64Cu-labeled supramolecular nanoparticles with different sizes (30 or 100 nm) into the front footpad of mice. The whole-body biodistribution and lymph node drainage studies demonstrated that the sizes of these supramolecular nanoparticles affected their in vivo characteristics.

4.5. Tissue Engineering

Figure 19. A) Schematic illustration of supramolecular fluorescent nanoparticles (SFNPs) formed from PEI-CD (19), CA-AD (20), mPEG-AD (21), and FA-AD (22) via β-CD/AD host–guest interaction. B) Confocal laser scanning microscopy (CLSM) images of HeLa cells that incubated with SFNPs without folate (top panel), and SFNPs with folate (bottom panel) at 37 °C for 1 h. Nuclei were stained with DAPI. Reproduced with permission.[314] Copyright 2012, American Chemical Society.

non-ionizing radiation source, and high resolution and discrimination of soft tissue, MRI has been widely used for noninvasive bioimaging in human body. Currently, much effort has been devoted to developing highly sensitive MRI contrast agents. In addition to conventional MRI contrast agents, diverse supramolecular MRI contrast agents have also been reported to date. In a study, Tseng and co-workers[318] prepared a novel class of supramolecular-nanoparticle-based contrast agents through the self-assembly of Gd3+-DOTA/CD-grafted PEI, AD-grafted poly(amido-amine) dendrimer, and AD-grafted PEG. In their design, by tuning the mixing ratios of these molecular units, a small library of Gd3+-DOTA-containing supramolecular nanoparticles could be generated with distinct sizes and crosslinking degrees of the corresponding hydrogel networks, resulting in a broad performance diversity of the relaxivity in these nanoparticles ranging from 4.19 s−1 m M−1 to 17.3 s−1 m M−1. The resulting Gd3+-DOTA nanoparticles displayed great enhancement of sensitivity and relaxivity compared to that of

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Tissue engineering is a promising strategy to achieve local regeneration of lost or malfunctioning tissues and organs by culturing a patient's own cells on a polymer matrix.[326,327] The biological environment and cell-biomaterial interaction are the utmost important for the functioning of the implanted biomaterials. Ideal biomaterials not only effectively combine tunable mechanical performances, regulation of the degradability and the ease for bioactivity incorporation, but also have the ability to mimic the natural environment into which the biomaterials are brought.[328] Supramolecular chemistry provides a versatile and powerful platform for the design and development of functional supramolecular polymers with excellent biofunctionality, showing great potential as biocompatible scaffolds that can support, guide, and stimulate developing tissues. In the past decade, a number of bioactive supramolecular polymers formed by the self-assembly of small synthetic molecules based on highly directional, reversible, non-covalent interactions, has been extensively developed and used for tissue engineering.[160,161,329–338] This section will briefly describe the applications of bioactive supramolecular systems in tissue engineering. In recent years, bioactive supramolecular nanostructures assembled from peptide-based building blocks have displayed great potential as dynamic biomaterials for tissue-engineering applications. Stupp and Zhang pioneered studies on the selfassembly of peptide amphiphiles. The resulting peptide-based supramolecular nanofibers, with varying morphology, surface chemistry, and bioactivity, were successfully applied for tissue engineering.[160,161,329,330] As an elegant example, Stupp and

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Differently, Meijer and co-workers achieved the applications of bioactive hydrogen-bonded supramolecular systems in tissue engineering. In a study, they fabricated bioactive supramolecular materials by simply mixing UPy-modified oligocaprolactones (23) with Upy-functionalized cell-adhesion-promoting UPy-Gly-Arg-Gly-Asp-Ser (UPy-GRGDS) (24) and synergistic UPyPro-His-Ser-Arg-Asn (UPy-PHSRN) peptide sequences (25) (Figure 21A).[334] These obtained biomaterials with favorable mechanical properties, biodegradability, and biocompatibility, are able to be readily processed into different morphological scaffolds such as meshes, films, and grids, facilating the proliferation of fibroblast cells. The in vitro results showed strong, specific binding of fibroblast Figure 20. A) Molecular structure of an IKVAV-incorporated peptide amphiphile and its self- cells to the UPy-decorated supramolecular assembly into nanofibers. B) SEM image of the resulting nanofiber network formed by the biomaterials containing both UPy-peptides addition of cell media (DMEM) to the aqueous solution of peptide amphiphile. C) Percentage (Figure 21B). A remarkable effect was of total cells that differentiated into neurons after 24 h in nanofiber networks with different observed in vivo where the formation of giant amounts of IKVAV-PA and EQS-PA (solid line) or in EQS-PA nanofiber networks containing different amounts of soluble IKVAV peptide (dashed line). The inset presents immunocytochem- cells at the interface between bioactive mateistry of a NPC neurosphere entrapped in an IKVAV-PA nanofiber network at 7 days. Reproduced rials and tissues was triggered (Figure 21C), indicating that both UPy-peptides played an with permission.[160] Copyright 2004, American Association for the Advancement of Science. important role in the signaling and infiltration of macrophages, as well as in the fusion to giant cells. Later, they further developed copolymeric UPyco-workers investigated the possibility of using supramolecular systems consisting of bifunctional and chain-extended olinanofibers for tissue engineering of nerves.[160] In their system, gocaprolactones, thereby effectively tuning their mechanical neural progenitor cells were firstly enclosed within a threeperformances and in vivo tissue response.[335] The resulting dimensional supramolecular nanofiber network formed by selfassembly of peptide amphiphiles (Figure 20A,B). Compared supramolecular copolymeric materials showed a gentle tissue with soluble peptide or laminin, the artificial nanofiber scaffold response along with the thin capsule formation upon implanled to extremely rapid and selective differentiation of neural tation. This supramolecular copolymer might be an ideal scafstem cells into neurons, restraining the growth of astrocytes. fold material for soft-tissue engineering owing to its flexibility Rapid selective differentiation was completed through introducand diminished fibrous tissue formation. Recently, Dankers tion of this IKVAV peptide into the supramolecular nanofibers et al.[336] reported living renal membranes consisting of hiercapable of displaying up to 1015 IKVAV epitopes cm−2. The archical supramolecular biomembranes and primary human tubular epithelial cells. The hydrogen-bonded supramolecular feasible epitope density surrounding the cells played a crupolymers self-assembled into nanoscale fibers, and, thereby, cial role in the neuron differentiation, and thus the selective bioactivity was introduced into these supramolecular nanofibers differentiation required assemblies consisting of nearly 50% by supramolecular intercalation of UPy-modified extracellular of the peptide amphiphile molecules used to produce a filamatrix-derived peptides, leading to the formation of supramomentous network included the biological signal (Figure 20C). lecular biomembranes composed of bioactive nanofibers by In another example, supramolecular nanofibers containing a electrospinning. Furthermore, these bioactive supramolecular peptide sequence with a high binding affinity to heparin have membranes induced primary human tubular epithelial cells to been used to promote growth of blood vessels.[161] Heparin form compact monolayers, even after prolonged culturing for binding to angiogenic growth factors can be used to nucleate 19 days. Moreover, various CD-based supramolecular hydrogel the self-assembly of the nanostructures from peptide amphisystems have also been developed as bioactive supramolecular philes, producing rigid nanofibers that exhibit heparin chains materials for tissue engineering.[337,338] to orient proteins for cell signaling. In vivo, the formation of extensive new blood vessels is stimulated by the resultanting heparin-functionalized supramolecular nanofibers in the rat cornea. In parallel, Zhang and co-workers introduced β-sheet4.6. Biomimetic Chemistry forming peptides inspired by nature to produce supramolecular nanofiber scaffolds, which could be used for entrapment Biomimetic chemistry, which refers to a method of scientific of hippocampal neural cells,[331] neural cell adhesion/differeninquiry that involves mimicking the laws of nature to create new substances or structures, has become a blossoming tiation and extensive neurite outgrowth,[332] as well as differfield.[339,340] Inspired by nature, a vast number of biomimetic entiation of putative liver progenitor cells into hepatocyte-like [ 333 ] spheroid structures . supramolecular structures have been widely explored, aimed at

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REVIEW Figure 21. A) The modular approach for preparing bioactive supramolecular materials with versatile properties via simply mixing UPy-polymers (23) with different UPy-functionalized biomolecules (24, 25). B) Fibroblast cell adhesion and spreading in vitro on different drop-cast films consisting of mixtures of PCLdiUPy with both UPy-GRGDS and UPy-PHSRN (left panel) or PCLdiUPy alone (right panel) after 48 h for cell culturing without FBS. C) In vivo behavior of bioactive supramolecular polymeric materials. Solution-cast supramolecular PCLdiUPy films with UPy-GRGDS and UPy-PHSRN peptides (left panel) and without peptides (right panel) were subcutaneously implanted in male rats after 10 days. Reproduced with permission.[334] Copyright 2005, Nature Publishing Group.

revealing the mechanisms of many fascinating biological processes in nature.[341] Supramolecular assemblies not only show unique structure and specific functions, but also have the ability to achieve reversible switching of structures and properties under exposure to certain external stimuli, making them excellent model systems for biomimetic applications. This section mainly presents the recent progress in biomimetic chemistry, such as cell signaling with bioactive supramolecular polymers, vesicle fusion and fission, and other biomimetic hierarchical structures. In cells, the cell cytoskeleton composed of supramolecular filaments or microtubules plays a key role in many cellular processes. The reversible association of proteins dynamically generates and dissolves a framework of rigid filaments within microscopic gels. This fascinating process in which supramolecular structures within the cytoskeleton form and depolymerize rapidly not only controls cell migration, attachment, and division, but also provides a route for internal delivery of molecules to specific compartments.[342] Inspired by cells, a number of cytomimetic supramolecular structures have been created to achieve dynamic functions.[343] As discussed above, bioactive supramolecular polymers exhibit great potential for effective cell signaling, thereby providing an opportunity to cure diseases and improve quality of life through regenerative medicine. Benefiting from their dynamic and reversible nature, artificial supramolecular biomaterials that display multiple signals

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to receptors in high-density and highly directed geometry could be easily reconstructed by the cells to fit the necessary geometry after implantation in the human body. One typical example is rigid supramolecular filaments that display spatial signals to receptors on the cell surface as well as self-adaptive ability to achieve high binding affinities of receptors.[8] Synthetic vesicles have been proven to be available model systems to mimic the structural and dynamic features of cells, as well as to disclose the mechanisms of cellular processes, including adhesion, fusion, fission, endocytosis, budding, and birthing.[344–346] In 2005, our group reported a real-time membrane fusion induced by ultrasonication.[347] After the ultrasound treatment, two apposed hyperbranched polymeric vesicles fused with each other. The real-time fusion process of two vesicles contained four successive stages: membrane contact, central wall formation, symmetric extending of the fusion pore, and complete fusion. The study indicated that close apposition of membranes and small perturbations sufficed to trigger fusion, and protein was not necessary during this membrane fusion process. Subsequently, we further investigated a “cooperative fission” process of a daughter vesicle inside a mother vesicle by altering the osmotic pressure on the addition of glucose into the vesicular solution.[348] Recently, we achieved a largescale cytomimetic vesicle aggregation process using microsized cell-like vesicles as the building blocks. In this system, β-CD/ Azo host–guest recognition was utilized as the driving force

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to induce vesicle aggregation. The resulting vesicle aggregates could be reversibly disassembled and reformed upon alternative UV and visible irradiation.[349] Aside from the aforementioned cytomimetic assemblies, a collection of examples of other biomimetic hierarchical structures have been reported recently. As inspired by jellyfish, we constructed a new type of self-assembling vesicle, which showed a pH-triggered “breathing” behavior accompanied by reversibly switchable fluorescence properties (Figure 22A).[350] The vesicles were fabricated by the aqueous self-assembly of an amphiphilic diblock copolymer of PEG-b-poly(dimethylamino-azobenzene) (PEG-b-PDMA-Azo) (26) (Figure 22B). In our design, the DMAAzo groups not only showed the characteristics of aggregationinduced emission,[351] but also conferred pH-responsiveness to the vesicles. Under acidic conditions (pH of 4), the vesicles breathed in, accompanied by vesicle swelling and vesicle-wall thinning. Inversely, under alkaline conditions (pH of 12), the vesicles breathed out, accompanied by vesicle shrinking and vesicle-wall thickening (Figure 22C). During the “breathing” process, the fluorescence was quenched when the vesicles breathed in, while a strong fluorescence was emitted when the vesicles breathed out (Figure 22D). The jellyfish-like breathing and light-emitting behavior could be achieved reversibly many times upon alternating addition of HCl and NaOH. This work expanded cytomimetic chemistry from single morphological transformation of membranes to a combination of cytomimetic morphology with the cooperative function expression.

In another example, following the skeletal muscle protein titin's modular design, Guan and co-workers[352] fabricated the first biomimetic modular polymer (27) using the quadruple hydrogen bonding UPy motif as the modular-domainforming mimic of the Ig domains in titin, which displayed a rare combination of high toughness, high modulus, and adaptive properties involving self-healing and shape-memory (Figure 23A). The proposed molecular mechanism for such an incredible combination of mechanical properties and adaptive behaviors in this supramolecular polymer is illustrated in Figure 23B. The applied stress firstly led to the unfoldment of UPy dimer modules, and then the resulting unfolded UPy units could dimerize to form a temporary supramolecular network upon cooling this polymer and removing the stress. With an increase in the temperature of this system, the newly formed interchain UPy dimers gradually reverted back to their original cyclic self-dimerized state, further regaining their initial sizes and properties. This biomimetic modular system incredibly combined high toughness and self-healing properties in a single material, something that had proven extremely difficult to realize in practice. Additionally, a hemin-encapsulated supramolecular hydrogel system has also been developed as an artificial enzyme to mimic peroxidase.[353] The supramolecular hydrogels not only protect the hemin by preventing dimerization and degradation, but also facilitate the catalytic reaction by providing nanoporous diffusion channels to allow the transport of substrates.

Figure 22. A) The breathing processes of jellyfish-inspired vesicles accompanied with highly reversible fluorescence quenching and recovery. B) Schematic illustration of an amphiphilic block copolymer of PEG-b-PDMA-Azo (26) and the resulting vesicular structure. C) Reversible size change of the vesicles upon alternating addition of HCl (pH 4) and NaOH (pH 12). D) Reversible fluorescence change of the vesicles at 536 nm upon alternating addition of HCl (pH 4) and NaOH (pH 12). Reproduced with permission.[350] Copyright 2012, Wiley-VCH.

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In this review, we have highlighted the current progress in the exploitation of functional supramolecular polymers, including design and synthesis strategies, properties and functions, and their applications in various applications in the biomedical field. The resultant functional supramolecular polymers not only display specific functions, but also have the ability to undergo a dynamic regulation of structure, morphology, and function under exposure to diverse external stimuli, thereby offering a flexible and robust platform for the design and preparation of smart supramolecular polymeric materials that perfectly combine dynamics and molecular order to realize multiple functions. From a structural perspective, both noncovalent interactions and topological structures have a decisive impact on the physicochemical properties and functions of supramolecular polymers, as well as the release behavior and biological activity of the resulting supramolecular delivery vehicles. In addition, functional supramolecular polymers have some unusual superiority, including inherent degradable polymer backbones, smart responsiveness to various biological stimuli, and the ease for the incorporation of multiple biofunctionalities (e.g., targeting and bioactivity), thereby showing great potential in a wide range of applications in the biomedical field, such as drug delivery, gene transfection, protein delivery,

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5. Summary and Outlook

bioimaging and diagnosis, tissue engineering, and biomimetic chemistry. Currently, great progress has been made in the field of functional supramolecular polymers for biomedical applications. However, this area still faces several key challenges. Firstly, the functionality of current supramolecular polymers is still relatively simple and monotone, and, thereby, the design and development of multiple and sophisticated functional supramolecular polymers have become urgent and indispensable. Secondly, a large number of supramolecular polymers constructed from macromolecular building blocks have been widely used in a wide range of applications in the biomedical field, whereas the biomedical application of small-molecule-based supramolecular polymers has not been well achieved up to now, owing to their poor stability and weak mechanical properties. Thirdly, the majority of functional supramolecular polymers have only been used for in vitro biomedical applications, and thus there is still a long way to go before their application in clinical diagnosis and therapy can be achieved in the future. Therefore, the relevant research in this area is still far from sufficient, and much more work needs to be done. In particular, it is well expected that multidimensional and multifunctional supramolecular polymers will be constructed via hierarchical organization by utilization of multiple non-covalent interactions. In addition, functional hybrid supramolecular polymeric materials

Figure 23. A) Molecular structure of a titin-mimicking linear modular supramolecular polymer (27). B) Schematic representation of proposed molecular mechanism for a rare combination of mechanical properties and adaptive properties based on the reversible rupture of intramolecular hydrogen bonding. Reproduced with permission.[352] Copyright 2009, American Chemical Society.

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by integration of supramolecular polymer and inorganic structures may display unexpected advantages of architectures, properties, and functions for bioapplications in the near future.

[28] [29]

Acknowledgements

[30]

The authors thank the National Basic Research Program (2012CB821500, 2013CB834506) and China National Funds for Distinguished Young Scientists (21025417) for financial support. Received: July 4, 2014 Revised: August 17, 2014 Published online:

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Functional supramolecular polymers for biomedical applications.

As a novel class of dynamic and non-covalent polymers, supramolecular polymers not only display specific structural and physicochemical properties, bu...
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