Cyclodextrin‐Based Pseudocopolymers and Their Biomedical Applications for Drug and Gene Delivery

Abstract

Cyclodextrin (CD)‐based pseudocopolymers draw on the host–guest inclusion complex properties of CDs, particularly β‐CD, to form noncovalent connections with compatible guest molecules. This approach enhances the structural versatility and biocompatibility of the resulting polymer blocks. Host–guest chemistry enables the assembly of sophisticated architectures, such as comb‐like grafts, star structures, and dendrimer‐like forms, which are engineered for targeted, stimuli‐responsive, and sustained drug release. Several innovative systems, including pH‐sensitive micelles, redox‐responsive nanoparticles, and dual‐responsive hydrogels that provide high drug‐loading capacity, controlled release, and tumor‐targeted delivery, are discussed. Applications in drug and gene therapy are highlighted, where CD‐based pseudocopolymers increase drug loading and transfection efficiency, reduce cytotoxicity, and facilitate the precise delivery of therapeutic agents, such as DNA and small interfering RNA. This review showcases the potential of CD‐based pseudocopolymers as adaptable platforms for advanced drug and gene delivery, addressing numerous challenges posed by biological barriers, multidrug resistance, and the need for targeted therapies through rational system design. Future directions emphasize optimizing these systems for clinical translation, focusing on refining synthetic methodologies, enhancing molecular modularity, and achieving a deeper understanding of their biological compatibility.

Host–guest interactions between cyclodextrin (CD) and compatible guest molecules enable the formation of diverse architectures, such as multiblock and linear–star copolymers as well as advanced systems like redox‐responsive nanoparticles. This structural versatility facilitates precise system design, conferring multifunctionality for controlled drug release and tumor‐targeting, relevant in overcoming key challenges in drug and gene delivery, including biological barriers and multidrug resistance.

1. Introduction

Block copolymers (BCPs) are macromolecules that comprise at least two distinct polymeric blocks joined covalently. BCPs are categorized according to their construct arrangements, such as diblock (A–B), triblock (A–B–A or A–B–C), pentablock, star, and graft copolymers.^{[ 1} , ² , ^{3 ]} Owing to the unique combinations of polymer blocks, they can exhibit different phenomena in disparate solvents or environments.^{[ 4} , ⁵ , ⁶ , ⁷ , ⁸ , ^{9 ]} Specifically, the self‐assembly of amphiphilic BCPs in aqueous solutions has garnered wide interest in biomedicine and biomaterials.^{[ 10} , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ^{17 ]} By exploiting this unique phenomenon, various biomedical applications, such as drug delivery,^{[ 18 ]} gene delivery,^{[ 19 ]} and tissue engineering,^{[ 20 ]} have been explored over the years. Notably, the self‐assembly of BCPs in aqueous solutions can adopt distinct morphologies depending on the block composition (e.g., micelles, spheres, rods, and vesicles).^{[ 21} , ²² , ²³ , ^{24 ]} The ability to take on different morphologies via self‐assembly is also a testament to the endless potential biomedical applications of BCPs.

Advancements in polymer science, such as controlled living radical polymerization and coupling strategies, have enabled the generation of diverse macromolecular architectures.^{[ 25 ]} This is made possible through rational selection and precise control over the functionality of initiators, the type and order of monomer insertion, and the ratio and length of individual polymer blocks.^{[ 26} , ²⁷ , ²⁸ , ^{29 ]} Consequently, innumerable copolymers with distinct topologies and physicochemical properties can be synthesized. To this end, it is also conceivable to confer multiple functions, such as stimuli responsiveness and ligand targeting, to BCPs. Multifunctional properties can be imperative in the design of delivery systems to overcome difficult physiological barriers.^{[ 30} , ^{31 ]} Despite rapid progress in polymerization techniques, accessing complex macromolecular architectures is still challenging because many laborious and time‐consuming intermediate steps are needed. This slow and tedious synthesis process of new complex BCP variants remains a major impediment to clinical trials and the commercialization of novel BCP‐based biomaterials.

Cyclodextrins (CDs) are cyclic oligosaccharides produced from the enzymatic breakdown of starch.^{[ 32 ]} They commonly consist of d‐glucose units joined by α‐1,4‐glycosidic bonds with 6, 7, and 8 units corresponding to α‐, β‐, and γ‐CD, respectively. CDs take the form of an inverted cone with a hollow cavity. The external surface of CDs is hydrophilic because of the presence of many hydroxyl groups. The hydroxyl groups can be grouped into primary (on the narrower upper rim) or secondary (on the wider lower rim) groups. These hydroxyl groups allow for ease of modification as well as stereoselective reactivity, thus enabling precise control over the position of conjugation and, consequently, more design options for novel architectures.^{[ 33} , ^{34 ]} In contrast to their exterior, the interior of CDs is nonpolar. This hydrophobic inner cavity can function as a host and take in various guest molecules, forming supramolecular inclusion complexes. β‐CD and adamantane are among the most studied host–guest pairs because of their strong binding affinity in water.^{[ 35 ]} However, many other guest molecules are being examined to introduce stimuli‐responsiveness, targeting, or hierarchical assembly properties (as discussed in later sections).

Fundamentally, the use of CDs in polymer design is grounded in classic supramolecular chemistry principles. Since the 1960s, chemists have recognized that reversible host–guest interactions can drive the assembly of complex systems.^{[ 36 ]} Early landmark studies by Breslow and co‐workers in the 1970s demonstrated that modified CDs could act as enzyme mimics, catalyzing reactions by providing an enzyme‐like binding pocket and catalytic functionality.^{[ 37} , ^{38 ]} These successes established the thermodynamic and structural basis for CD host–guest chemistry, namely, that CD complexes achieve significant binding affinity yet remain reversible and responsive to environmental conditions. In the polymer realm, Harada and Kamachi's seminal work in 1990 showed that α‐CD rings can spontaneously thread onto polymer chains to form “pseudopolyrotaxanes.”^{[ 39 ]} By capping the chain ends with bulky stoppers, such assemblies were converted into true polyrotaxanes wherein CD macrocycles are trapped on the polymer but retain mobility, a concept later extended to figure‐of‐eight cross‐links where two bridged CDs serve as a movable junction between polymer chains.^{[ 40 ]} Together, these foundational examples from enzyme‐mimicking catalysts to freely sliding cross‐linkers illustrate how reversible CD–guest interactions can be harnessed to build noncovalent polymer architectures. This supramolecular chemistry framework forms the foundation of CD‐based pseudo‐BCPs, providing a molecular‐level rationale for their dynamic behavior and modular assembly.

Pseudo‐BCPs can be formed when two distinct polymeric blocks with suitable strong‐binding host and guest group terminals are joined via noncovalent interactions. Many novel polymeric systems have been developed by exploring different orthogonal combinations of CD‐based hosts and the corresponding guests.^{[ 41} , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ^{46 ]} Interestingly, the formation of inclusion complexes occurs rapidly under aqueous conditions—an attractive property to expedite the process for rational design and optimization of multifunctional delivery systems. In this review, we highlight the development of CD‐based pseudo‐BCPs via the host–guest strategy. The focus will be on how different groups have exploited this strategy to access complex macromolecular architectures as well as impart multifunctionalities for drug and gene delivery applications (Figure 1 ). It is worth noting that this review does not cover pseudorotaxane systems, in which native CDs are physically threaded onto BCP backbones (e.g., Pluronic F127 or 17R4) without covalent conjugation. While these assemblies also leverage CD‐based inclusion and have shown promise in delivery applications, their mode of construction based on topological entrapment rather than defined host–guest conjugation falls outside the scope of this article. Instead, we focus on architectures in which one or both polymer components are chemically modified with CD or guest moieties to enable modular, reversible assembly through specific host–guest recognition.

Figure 1.

Schematic representation of diverse macromolecular architectures enabled by host–guest interactions between cyclodextrin and compatible guest molecules, with a focus on rational system design for drug and gene delivery, as well as emerging uses in imaging and diagnostics.

2. Guest Molecules in Cyclodextrin‐Based Pseudocopolymers

CDs are cyclic oligosaccharides commonly used as hosts in the formation of pseudo‐BCPs because of their unique cavity sizes, which enable selective host–guest interactions. Among them, β‐CD is the most widely employed because its medium‐sized cavity accommodates a range of small‐ to medium‐sized guest molecules, making it especially desirable in drug delivery systems and polymer functionalization.^{[ 47 ]} By contrast, α‐CD has a smaller cavity, which favors the formation of pseudorotaxanes with linear polymers that can thread through its structure.^{[ 48} , ⁴⁹ , ^{50 ]} On the other hand, γ‐CD, with its larger cavity, is less frequently utilized because of its lower binding specificity but offers potential in specialized applications involving larger guest molecules.^{[ 51 ]} Overall, CDs play a pivotal role in host–guest chemistry because of their ability to form stable inclusion complexes, which are widely explored for applications in drug delivery, biosensing, and supramolecular assemblies. Representative association constants (K _a) of common guest molecules with various CD types, including the influence of stimuli such as pH or photoisomerization, are summarized in Table 1 . Common guest molecules include the following.

Table 1.

Association constants of representative guest molecules with cyclodextrins (α, β, and γ), including measurement methods and changes under stimuli such as ultraviolet (UV) light, pH, or redox. Abbreviations: Ka = association constant; UV–vis = ultraviolet–visible spectroscopy; ¹H NMR = proton nuclear magnetic resonance; HPLC = high‐performance liquid chromatography; N.A. = not applicable; N.S. = not stated.

Guest molecule	Cyclodextrin type	K a [M⁻¹]	Measurement method	Stimuli‐responsive	Stimulus type	Temperature [°C]	pH	Refs.
1‐Adamantanecarboxylic acid	α	2.3 × 102	Microcalorimetry	No	N.A.	25	7.22	[65]
Adamantane	β	1.91 × 103	UV–vis	No	N.A.	22	10.65	[66]
Adamantane‐1‐carboxylate	β	10.5–1.2 × 104	Conductance	No	N.A.	25	4–10	[67]
Adamantanecarboxylate	β	3.6 ± 2 × 104	Microcalorimetry	No	N.A.	Room temperature	N.S.	[68]
Adamantan‐1‐yl methylammonium ion	β	3 ± 0.6 × 104	UV–vis	No	N.A.	25	7	[69]
1‐Adamantanecarboxylic acid	γ	5 × 103	Microcalorimetry	No	N.A.	25	7.22	[65]
Azobenzene (trans, untriggered)	α	2 × 103	1H NMR	Yes	UV, 365 nm	N.S.	N.S.	[70]
Azobenzene (trans, untriggered)	β	7.7 × 102	1H NMR	Yes	UV, 365 nm	N.S.	N.S.	[70]
Azobenzene (cis, after UV)	α	3.5 × 101	1H NMR	Yes	Light, 430 nm	N.S.	N.S.	[70]
Azobenzene (cis, after UV)	β	2.8 × 102	1H NMR	Yes	Light, 430 nm	N.S.	N.S.	[70]
Ferrocenylalkyldimethylammonium	α	4.5 × 102	Microcalorimetry	Yes	Redox	25	6.5	[71]
(R)‐1‐ferrocenylethanol	α	1 × 102	HPLC	Yes	Redox	25	11.4	[72]
Ferrocenecarboxylate	β	2.14 × 103	Microcalorimetry	Yes	Redox	25	8.6	[73]
Ferrocenylalkyldimethylammonium	β	2.5 × 103	Microcalorimetry	Yes	Redox	25	6.5	[71]
Phenolphthalein	β	4.75 × 104	UV–vis	Yes	pH	25.3	9.94	[74]
Phenolphthalein	γ	3.14 × 103	UV–vis	Yes	pH	24.7	9.94	[74]
2‐amino‐5,6‐dimethyl‐benzimidazole	β	2.07 ± 0.08 × 103	Fluorescence lifetime	Yes	pH	25	N.S.	[75]
Cholesterol	β	1.7 x 104	UV–vis	No	N.A.	25	6.4	[76]
d‐phenylalanine	α	1.95 × 101	UV–vis and microcalorimetry	No	N.A.	25	11	[77]
l‐phenylalanine	α	1.58 × 101	UV–vis and microcalorimetry	No	N.A.	25	11	[77]
l‐phenylalanine	β	1.07 × 102	Microcalorimetry	No	N.A.	25	11.3	[78]
l‐phenylalanineamide	β	1.07 × 102	Microcalorimetry	No	N.A.	25	10.02	[79]

2.1. Adamantane

Adamantane, a polycyclic hydrocarbon, has a unique, symmetrical, cage‐like structure with significant steric bulk and hydrophobic properties. These characteristics make it a strong candidate for forming stable inclusion complexes with β‐CD, whose cavity size fits adamantane derivatives well.^{[ 52 ]} The hydrophobic interaction between adamantane and the nonpolar interior of β‐CD is enhanced by van der Waals forces, creating a durable complex that resists dissociation in aqueous environments. This stability, combined with adamantane compatibility with CD inclusion, enables its use in applications requiring sustained drug release, as well as in the construction of self‐assembled materials where reversible binding is advantageous.

2.2. Azobenzene

The defining feature of azobenzene is its ability to undergo reversible trans–cis isomerization in response to specific wavelengths of light. This switchable structure is particularly useful in host–guest chemistry with CDs, as the trans form of azobenzene fits well into the CD cavity, while the cis form disrupts this interaction. This light‐responsive behavior enables azobenzene–CD complexes to be used in applications such as photoresponsive drug delivery systems, where drug release can be triggered on demand with light, as well as in smart material design for the controlled assembly and disassembly of supramolecular structures.^{[ 53 ]}

2.3. Ferrocene

Ferrocene is a metallocene with a stable sandwich structure featuring an iron atom sandwiched between two cyclopentadienyl rings. Owing to its unique redox properties, ferrocene is ideal for use in CD‐based host–guest systems for electrochemical applications. When complexed with CDs, ferrocene retains its ability to undergo reversible oxidation and reduction, making CD–ferrocene complexes valuable in applications such as molecular switches, where electron transfer is essential, and in sensors, where electrochemical responsiveness can detect specific analytes.^{[ 54 ]} The stability provided by the CD complex can also protect ferrocene from degradation, enhancing its applicability in catalysis.

2.4. Phenolphthalein

Phenolphthalein is a pH‐sensitive organic molecule known for its distinctive color change across varying pH values, a property widely exploited in analytical chemistry as a pH indicator. In host–guest chemistry, phenolphthalein forms inclusion complexes with CDs, which can influence its colorimetric response. This ability to complex with CDs makes phenolphthalein valuable in pH‐responsive systems, where the host–guest interaction can provide controlled release under specific pH conditions.^{[ 55 ]} The inclusion of phenolphthalein in CDs has also been applied in biosensing, where pH changes in the environment can trigger a visible response, as well as in analytical assays where pH‐responsive release and binding are desired.^{[ 56 ]}

2.5. Benzimidazole

This nitrogen‐containing aromatic guest forms inclusion complexes with CDs, increasing their solubility and stability, which is especially useful for bioactive molecules. It is often employed in pharmaceuticals, aiding in drug solubilization and stability.^{[ 57 ]} The benzimidazole (BM) group can be protonated under acidic conditions, leading to changes in its charge, solubility, and affinity for the CD cavity. At higher pH values, the neutral form of BM fits well into the hydrophobic cavity of β‐CD, while at lower pH values, protonation increases its polarity, often weakening its interaction with CDs or even causing it to dissociate from the host.^{[ 58 ]} This pH responsiveness makes BM an effective guest for designing stimuli‐responsive systems, such as controlled drug release platforms, where release can be triggered by pH changes in the environment, or as part of switchable systems in drug delivery and sensing applications.

2.6. Cholesterol

Cholesterol, a complex sterol molecule with a rigid, hydrophobic tetracyclic structure, naturally interacts well with CDs, particularly β‐ and γ‐CD, to form stable host–guest complexes.^{[ 59 ]} The nonpolar, hydrophobic cavity of CDs is well suited to accommodate the bulky structure of cholesterol, increasing its aqueous solubility through encapsulation.^{[ 60 ]} This property is particularly useful in dietary and pharmaceutical formulations, where the limited water solubility of cholesterol can be a challenge. The CD–cholesterol complex also provides a useful model in biological research, particularly for studying cholesterol behavior within cellular membranes and its interactions with membrane proteins.^{[ 61 ]} In addition, this complexation is used to mimic the role of cholesterol in lipid bilayers and in the development of delivery systems that target lipid‐rich environments.

2.7. Phenylalanine

Phenylalanine, an aromatic amino acid, contains a benzyl side chain that can fit well within the CD cavity, allowing it to form stable inclusion complexes. This interaction with CDs is driven primarily by hydrophobic interactions between the phenylalanine phenyl ring and the inner cavity of the CDs, particularly β‐CD, owing to their compatible sizes.^{[ 62} , ⁶³ , ^{64 ]} These CD–phenylalanine complexes are beneficial for stabilizing and delivering bioactive peptides or amino acids, as they improve solubility, enhance stability, and protect sensitive amino acids from degradation. In pharmaceutical formulations, these complexes can improve the bioavailability of amino acid derivatives. In biochemical research, CD–phenylalanine complexes are valuable tools for investigating protein–ligand interactions and the structural roles of amino acids in protein folding and function.

3. Characterization of Cyclodextrin‐Based Inclusion Complexes

To confirm and characterize the formation of CD‐based inclusion complexes, a suite of analytical techniques is typically employed to validate host–guest interactions and assess the stability, composition, and structural orientation of the complexes. Each method provides a different perspective on interaction: some techniques elucidate the molecular structure and orientation, while others measure the binding strength and stability. The following overview presents key techniques for studying CD‐based inclusion complexes, highlighting their specific roles in confirming successful complexation.

3.1. 2D Nuclear Magnetic Resonance (NMR) Spectroscopy

2D NMR, particularly rotating‐frame overhauser enhancement spectroscopy (ROESY) or nuclear overhauser spectroscopy, is a powerful technique for investigating the spatial arrangement of host and guest molecules. For inclusion complexes, 2D NMR detects intermolecular interactions between the hydrogen atoms of CD and the guest molecule through cross‐peaks, which are indicative of the guest residing within the CD cavity. This approach allows detailed analysis of the binding orientation and interaction sites.

3.2. Optical Spectroscopic Techniques

Fluorescence spectroscopy measures fluorescence changes in either the CD or guest molecules upon complexation. When a fluorescent guest molecule forms a complex with CD, changes in fluorescence intensity, quenching, or emission shifts can indicate binding. Circular dichroism spectroscopy measures changes in the optical activity of chiral guest molecules within the chiral CD environment. Inclusion can induce characteristic shifts in circular dichroism spectra, providing insight into the binding strength and conformation. Ultraviolet (UV)–vis spectroscopy was used to monitor the changes in the absorbance of guest molecules with characteristic absorbance peaks. Upon complex formation, peak shifts or changes in absorbance intensity can confirm inclusion complex formation.

3.3. Competitive Binding Assays

Competitive binding is used to verify inclusion complex formation by introducing a secondary guest molecule with a known affinity for CD. Displacement of the primary guest or changes in spectroscopic signals upon competition reveals the binding affinities and the stability of the initial complex.

3.4. X‐Ray Diffraction Analysis

X‐ray diffraction (XRD) provides insight into the crystallographic structure of CD inclusion complexes. For solid‐state complexes, XRD analysis reveals characteristic changes in diffraction patterns due to the ordered structure of the host–guest complex, which is distinct from that of the CD or guest alone.

3.5. Differential Scanning Calorimetry

Differential scanning calorimetry was used to measure the thermal properties of the inclusion complex compared with those of pure CD and the guest. A successful complex typically shows altered melting points, phase transitions, or enthalpy changes, which confirms the encapsulation of the guest within the CD cavity. These thermal shifts indicate increased stability or protection of the guest molecule during CD. Each technique provides unique data, and a combination is often used to confirm and understand the complex's formation and structural characteristics comprehensively.

3.6. Isothermal Titration Calorimetry

Isothermal titration calorimetry (ITC) is a robust technique for directly quantifying the thermodynamic parameters governing CD‐based host–guest inclusion complexes. Unlike spectroscopic methods, ITC does not require labeling or structural modification of the host or guest molecules, making it highly suitable for characterizing native systems in solutions. ITC measures the heat change associated with each incremental injection of a guest molecule into a solution containing the CD host, allowing precise determination of the binding constant (K _a), enthalpy change (ΔH), entropy change (ΔS), and stoichiometry (n) of the interaction. These parameters provide detailed insight into the driving forces of complex formation, whether enthalpic (e.g., hydrogen bonding and van der Waals interactions) or entropic (e.g., hydrophobic effect and water release). For CD‐based pseudo‐BCPs, ITC can be exploited to optimize guest selection and host functionalization, particularly when designing systems with orthogonal binding motifs or competitive displacement mechanisms. Moreover, comparative ITC studies across various guest analogs or polymer conjugates can guide rational design by revealing subtle differences in affinity and complexation behavior under physiologically relevant conditions.

4. Various Architectures of Cyclodextrin‐Based Pseudocopolymers

4.1. Linear Multiblock

The simplest architectural form of pseudocopolymers is linear multiblock. The host CD is usually modified with a single linear polymeric chain on the primary face. The secondary face with the cavity is thus accessible as an interface to form complexes with complementary guest molecules attached to a different polymeric chain. The complexes then serve as noncovalent junctions to generate linear multiblock pseudocopolymers (Figure 2a). The uncomplicated construction of linear multiblock pseudocopolymers enables easier projection of copolymer properties via rational selection of individual polymer blocks.

Figure 2.

Representative examples of CD‐based pseudo‐BCPs with linear multiblock architecture. a) Basic construction of a linear multiblock pseudocopolymer. The guest molecule is modified with a single linear polymeric chain. The host CD is modified with a single linear polymeric chain on the secondary face. Reproduced with permission.^{[ 80 ]} Copyright 2011, American Chemical Society. b) Light‐sensitive linear pseudo‐BCP assembled from poly(ε‐caprolactone) (PCL)‐modified α‐CD and poly(acrylic acid) (PAA)‐modified trans‐azobenzene. The system exhibits reversible disassembly and assembly at different wavelengths. Reproduced with permission.^{[ 81 ]} Copyright 2011, The Royal Society of Chemistry. c) pH‐sensitive linear pseudo‐BCP assembled from poly(ethylene glycol) (PEG)‐modified BM and poly(l‐lactide) (PLLA)‐modified β‐CD. At neutral pH = 7.4, the linear pseudo‐BCP self‐assembled in water to form stable micelles. At acidic pH = 5.5, micelles destabilize and facilitate the release of encapsulated doxorubicin. Reproduced with permission.^{[ 82 ]} Copyright 2015, American Chemical Society. d) Pseudo‐triblock copolymer system assembled from poly(N‐(2‐hydroxypropyl)‐methacrylamide) (PHPMA)‐modified β‐CD and poly(N,N‐dimethylacrylamide) (PDMAAm)‐ or poly(N,N‐diethylacrylamide) (PDEAAm)‐modified guest molecules. When azobenzene is utilized as the guest molecule, the pseudo‐triblock copolymer system becomes responsive to both light and temperature. Reproduced with permission.^{[ 83 ]} Copyright 2013, American Chemical Society. e) Light‐induced reversible transition between pseudo‐diblock or pseudo‐triblock systems. Reproduced with permission.^{[ 84 ]} Copyright 2014, The Royal Society of Chemistry.

Pseudo‐diblock copolymer systems have been investigated by several groups. Voit and co‐workers reported the design of a pseudo‐diblock copolymer with alterable temperature‐sensitive properties by introducing a second water‐soluble block.^{[ 80 ]} The dual system consists of a β‐CD–poly(N‐isopropylacrylamide) (β‐CD–PNIPAAm) host and an adamantane‐modified poly(2‐methyl‐2‐oxazoline) guest synthesized via atom transfer radical polymerization (ATRP) and cationic ring‐opening polymerization (ROP), respectively. With the addition of the second block, the authors found that the overall hydrophilicity was enhanced, resulting in higher temperature requirements to achieve a reversible phase change. Furthermore, interesting smart systems can be generated by utilizing a responsive guest molecule instead of adamantane. For example, Yuan and co‐workers demonstrated a light‐sensitive system by incorporating poly(ε‐caprolactone)–α‐CD (PCL–α‐CD) as the host and poly(acrylic acid)–trans‐azobenzene (PAA–tAzo) as the guest (Figure 2b).^{[ 81 ]} The host and guest homopolymers were synthesized via ROP and reversible addition–fragmentation chain‐transfer (RAFT) polymerization, respectively. In the absence of light stimuli, the host–guest system self‐assembles in water to form nanotubes that are stable for at least 3 months. Irradiating the system with UV light causes reversible disassembly of the host–guest complex due to the UV‐induced isomerization of tAzo to cis‐azobenzene. The larger cis isoform is incompatible with the host cavity and dissociates, breaking the system into its individual host and guest components. This light‐sensitive construct shows great promise as a smart release system because it releases payloads only upon stimulation. In another study led by He and co‐workers, a pH‐sensitive host–guest micellar system was designed by employing the host β‐CD–poly(l‐lactide) (CD–PLLA) and the guest BM‐modified PEG (PEG–BM) (Figure 2c).^{[ 82 ]} At physiological pH, the supramolecular system forms stable spherical micelles capable of drug loading. As the pH is reduced to acidic levels, the micelle destabilizes due to the dissociation of the pH‐sensitive BM moieties from the host–guest complex, instead forming large aggregates. The authors further showed that the system has tunable drug release behaviors at distinct pH values.

In addition to pseudo‐diblock systems, pseudo‐triblock systems have also been explored. Barner‐Kowollik and co‐workers reported a pseudo‐ABA triblock copolymer based on a host CD–poly(N‐(2‐hydroxypropyl)‐methacrylamide) (CD–PHPMA) and guests containing either poly(N,N‐dimethylacrylamide) (PDMAAm) or poly(N,N‐diethylacrylamide) (PDEAAm) blocks terminated by adamantane or azobenzene (Figure 2d). When azobenzene is utilized to form host–guest complexes, the pseudo‐triblock system becomes sensitive to both the temperature and the UV light properties of PDMAAm/PDEAAm and azobenzene, respectively. Heating increases the tendency for aggregation while UV stimulation causes reversible disassembly of the pseudo‐triblock constructs.^{[ 83 ]} Tian and co‐workers devised a convenient method to fabricate polymeric nanospheres with a hollow core.^{[ 85 ]} This method utilizes reversible light‐regulated host–guest system assembly. The host polymer is a β‐CD‐capped poly(2‐(diethylamino)ethyl methacrylate) (β‐CD–PDEA) while the guest is an Azo‐capped poly((itaconoyloxy)ethyl methacrylate)‐block‐PNIPAAm copolymer. The host and guest were prepared via ATRP. The resulting pseudo‐triblock system self‐assembles in water under alkaline conditions to form nanospheres with PDEA as the core owing to its insolubility at high pH values. The authors then cross‐linked the shell layer via a UV cross‐linker. After dialyzing against neutral deionized water and UV irradiation, the light‐sensitive guest block is removed, thus forming a hollow core in the cross‐linked nanospheres. Since the shell comprises two smart blocks, the hollow nanospheres can be stimulated by changes in pH and temperature to achieve reversible swelling and deswelling properties. This smart property can be attractive for controlled drug delivery applications. Another creative use of the pseudo‐triblock system was presented by Zhang and co‐workers (Figure 2e).^{[ 84 ]} In this system, the light‐sensitive host–guest complex enables a switchable transition between triblock and diblock architectures by controlling the wavelength of the light used to irradiate the system (365 or 450 nm).

4.2. Comb‐Like Grafts

Comb‐like graft copolymers with side chains extending out along the main polymer backbone present a versatile approach to inserting several functionalities into one copolymer system. This system design preserves the overall bulk properties but enables more precise modulation for disparate applications, for example, by introducing cell‐targeting moieties or stimuli‐sensitive side chains. In comb‐like pseudocopolymer systems, the main polymer backbone is usually modified with pendant host or guest molecules. The side polymer chains are then capped with a complementary molecule (host/guest) and are grafted onto the main polymer backbone via noncovalent host–guest coupling.

One of the earliest comb‐like pseudocopolymer systems was shown through Bernard et al.’s collaborative work.^{[ 91 ]} The host polymer consists of a poly(propargyl methacrylate) backbone functionalized with alkyne groups. The backbone is then decorated with pendant β‐CD groups via copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC). On the other hand, the guest polymer is a mono‐adamantyl‐modified PAA (Ad–PAA). Under an aqueous environment, an equimolar ratio of β‐CD:Ad leads to spontaneous assembly of the host and guest polymers, producing a comb‐like pseudocopolymer system. The comb‐like system assembly was verified through 2D ¹H NMR and dynamic light scattering (DLS) studies. Furthermore, the authors demonstrated the reversibility of the host–guest coupling through a competitive host study. The grafting of hyperbranched polymers onto a linear polymeric backbone via the host–guest method has been demonstrated by Frey and co‐workers.^{[ 86 ]} In this comb‐like pseudopolymer system, the host polymer is a β‐CD‐decorated PHPMA synthesized through RAFT polymerization, and the guest is a mono‐adamantyl‐modified PEG‐block‐hyperbranched poly(glycerol) (Ada–PEG‐b‐hbPG) copolymer prepared through sequential ROP (Figure 3a). The host–guest association constant and molecular weight of the grafted hbPG were negatively correlated, likely because of the steric hindrance conferred by the degree of branching. This phenomenon was further confirmed by the addition of a PEG linker, which resulted in elevated association constant values. In an intriguing way to visualize the self‐assembly of the host–guest system in aqueous solutions, Ritter and co‐workers presented a comb‐like pseudocopolymer system that is based upon the characteristic color change of phenolphthalein.^{[ 55 ]} The host polymer is a β‐CD‐capped PDEAAm (β‐CD–PDEAAm) prepared from RAFT polymerization and CuAAC while the guest polymer is a random copolymer of N,N‐diethylacrylamide and N‐(2‐hydroxy‐5‐(10(4‐hydroxyphenyl)‐3‐oxo‐1,3‐dihydroisobenzofuran‐1‐yl)benzyl)acrylamide (PDMA‐stat‐PPA) synthesized via RAFT polymerization. The color of the PPA‐containing guest copolymer changes from colorless to pink in a basic solution. Upon host–guest complexation with β‐CD, PPA undergoes a slight conformational transition that results in decolorization of the solution, thus providing direct evidence of host–guest self‐assembly.

Figure 3.

Representative examples of CD‐based pseudo‐BCPs with a comb‐like graft architecture. a) A β‐CD‐decorated linear PHPMA backbone was grafted with Ada–PEG‐b‐hyperbranched poly(glycerol) (hbPG) copolymers through host–guest interactions. Reproduced with permission.^{[ 86 ]} Copyright 2013, American Chemical Society. b) A temperature‐sensitive graft pseudocopolymer was constructed from poly(β‐CD) and Ad–P(2‐(2‐methoxyethoxy) ethyl methacrylate (MEO₂MA)‐co‐OEGMA). The graft pseudocopolymer exhibited temperature‐reversible aggregation. Reproduced with permission.^{[ 87 ]} Copyright 2014, The Royal Society of Chemistry. c) A novel comb‐like poly(organophosphazene) hydrogel system was developed utilizing β‐CD‐modified and adamantyl‐modified poly(organophosphazene) (PPhos–β‐CD and PPhos–Ad), which exhibited host responsiveness, with its hydrogel network disrupted upon the addition of unmodified β‐CD. Reproduced with permission.^{[ 88 ]} Copyright 2014, American Chemical Society. d) A thermoresponsive comb‐like pseudocopolymer system comprising Ad–poly(oligo(ethylene glycol) methacrylate) (POEGMA) and pendant‐grafted PGCD, forming tunable micellar assemblies above its lower critical solution temperature (LCST) and water‐soluble aggregates below, with thermosensitivity adjustable via the host–guest molar ratio. Reproduced with permission.^{[ 89 ]} Copyright 2015, Elsevier B.V. e) A light‐responsive comb‐like pseudocopolymer system incorporating β‐CD modified with PNIPAAm star side chains and interacting with azobenzene‐functionalized guest polymers enables tunable micelles and vesicles (28–300 nm) with temperature‐dependent phase transitions and UV‐triggered disassembly. Reproduced with permission.^{[ 90 ]} Copyright 2017, The Royal Society of Chemistry.

The introduction of stimuli‐sensitive side chains or cell‐targeting moieties onto comb pseudocopolymer systems has been explored by various groups. Lu and co‐workers developed a temperature‐responsive comb‐like pseudocopolymer system based on poly(oligo(ethylene glycol) methacrylate) (POEGMA).^{[ 87 ]} The host polymer is a bulky poly(β‐CD) polymerized from aminoethyl methacrylate β‐CD (PGCD) via free radical polymerization, and the guest system is a monoadamantyl‐modified copolymer of 2‐(2‐methoxyethoxy) ethyl methacrylate (MEO₂MA) and OEGMA, Ad–P(MEO₂MA‐co‐OEGMA), synthesized from an adamantane‐based macroinitiator via ATRP (Figure 3b). Notably, thermosensitivity can be modulated by varying the amount of MEO₂MA, which in turn impacts the reversible temperature‐induced aggregation profile. Allcock and co‐workers explored the development of two different poly(organophosphazene)‐based systems via a host–guest block‐building strategy.^{[ 88 ]} By assembling poly(organophosphazene) modified with several β‐CD groups along the backbone (PPhos–β‐CD) with monoadamantyl‐modified PPhos (PPhos–Ad), a novel comb‐like pseudocopolymer system capable of spontaneous hydrogel formation was developed (Figure 3c). The gel was found to be host‐responsive, as a competitive host study revealed that hydrogel networks were broken or disrupted when unmodified β‐CD solution was added before or after hydrogel formation. Although not shown by the authors, this novel PPhos‐based comb‐like pseudocopolymer system is expected to be temperature sensitive, possibly forming stronger hydrogel networks when heated. Another interesting study by Lu and co‐workers demonstrated a temperature‐sensitive comb‐like pseudocopolymer system involving POEGMA.^{[ 89 ]} The guest polymer Ad–POEGMA was synthesized via ATRP of MeO₂MA and OEGMA building blocks. Unlike common POEGMA‐based copolymers, Ad–POEGMA displayed unique thermosensitive properties. It forms a heterogeneous population of water‐soluble aggregates with particle radii ranging from 10 to 350 nm. Above its lower critical solution temperature (LCST), the guest polymer formed stable and homogenous aggregates with an average particle size of 181 nm. A separate host system to serve as a pendant grafted polymer (PGCD) was synthesized by polymerizing aminoethyl methacrylate β‐CD. The graft pseudocopolymer system was constructed by mixing the host and guest systems (Figure 3d). The pseudocopolymer system was shown to form stable micellar assemblies above its LCST and water‐soluble aggregates below its LCST. This thermoresponsiveness can be tuned by adjusting the host‐to‐guest molar ratio. A modular approach to gene delivery was demonstrated by Liu et al., which involves the use of a poly(β‐CD)‐based star polymer with disulfide‐linked poly(2‐(dimethylamino)ethyl methacrylate) arms (PCD–SS–PDMAEMA) as the host, featuring disulfide linkages that enable controlled DNA release in reducing environments.^{[ 92 ]} The guest polymer, composed of adamantyl‐terminated PEG–folic acid (Ad–PEG–FA), enhances biocompatibility, reduces nonspecific interactions, and provides folate receptor (FR)‐targeting capability. The host–guest interaction between β‐CD units and adamantyl groups allows the formation of stable nanosized polyplexes that are resistant to enzymatic degradation. This system demonstrates efficient gene transfection of FR‐positive cells, such as the KB cell line, for both plasmid DNA (pDNA) and small interfering RNA (siRNA), offering a versatile strategy for multifunctional gene delivery by overcoming various extracellular and intracellular barriers.

Notably, several groups have designed dual‐responsive drug delivery systems to confer even greater control and precision over drug delivery and release. One prominent example is the synthesis of light‐responsive supramolecular polymer brushes, where β‐CD is modified with star‐like side chains of the polymer PNIPAAm.^{[ 90 ]} The host interacts with azobenzene groups on the guest polymer backbone through host–guest interactions, enabling the formation of micelles and vesicles with tunable sizes from 28 to 300 nm (Figure 3e). By adjusting the ratio of β‐CD to azobenzene, these assemblies can be precisely controlled. Moreover, the supramolecular polymer brushes exhibit a temperature‐dependent phase transition, forming strawberry‐like superstructures at higher temperatures. The system also responds to UV light, which triggers the disassembly of micelles or vesicles, offering a platform for dynamic control over the assemblies. Another example involves the formation of vesicular structures from the interaction between chitosan‐graft‐β‐CD (CS‐g‐β‐CD) as the host polymer and a PEG‐b‐PCL–BM guest polymer.^{[ 93 ]} The host–guest interaction between β‐CD and BM facilitates the formation of amphiphilic supra‐assemblies with a hydrophobic membrane composed of PCL/β‐CD and a hydrophilic corona formed from PEG and CS. These vesicles exhibit high encapsulation efficiency for both hydrophobic (curcumin) and hydrophilic (doxorubicin) drugs, with drug loading efficiencies of 20.2% and 38.4%, respectively. The vesicles display pH‐ and temperature‐sensitive release behavior, with enhanced release under acidic or high‐temperature conditions, indicating superior cytotoxicity compared with that of free drugs. In a similar system, amphiphilic micelles with dual temperature and pH sensitivity were formed via a graft copolymer with a brush‐like structure.^{[ 94 ]} The host polymer, β‐CD‐star‐PMAA‐b‐PNIPAM, contains star side chains, which interact with the guest polymer PHEMA‐g‐(PCL–BM). These micelles, with an average size of ≈80 nm, demonstrate an optimal size for tumor targeting via the enhanced permeability and retention (EPR) effect. The micelles exhibit a LCST between 40 and 41 °C, allowing temperature‐sensitive drug release, while acidic conditions promote micellar dissociation. The system achieves a high encapsulation efficiency of 97.3% for doxorubicin (DOX), and in vitro studies confirmed excellent anticancer activity and biocompatibility against human breast cancer cells.

4.3. Star, Dendrimer‐Like, and Hyperbranched

Star, dendrimer‐like, and hyperbranched polymers are advantageous over their linear counterparts because of their unique branched structure, which allows for multifunctionality, enhanced self‐assembly, and improved stability. Star architecture facilitates the incorporation of different polymer segments, enabling tunable properties and higher loading capacities for drug delivery and other applications. These polymers exhibit reduced chain entanglement, leading to lower viscosity and increased stability of nanoscale assemblies while also allowing for responsive behavior to stimuli such as temperature and pH.

One notable approach to star polymer architectures involves the formation of miktoarm star polymers using β‐CD as the host polymer and adamantane‐modified guest polymers. In one example, RAFT polymerization was employed to synthesize β‐CD‐based miktoarm star polymers with PDMAAm and PDEAAm arms. The azide–alkyne cycloaddition reaction was used to introduce functional groups that allowed for efficient host–guest complexation with β‐CD (Figure 4a).^{[ 95 ]} The resulting supramolecular star polymers exhibited a remarkable ability to self‐assemble and disassemble in response to external stimuli such as temperature changes. The dynamic nature of these miktoarm stars was demonstrated through reversible phase transitions that could be monitored via DLS and 2D NMR spectroscopy. This tunability makes these star polymers highly useful for applications where precise control over assembly and disassembly is needed, such as in drug delivery systems that respond to physiological conditions. In another example, the construction of star‐shaped ABC terpolymers was achieved via molecular recognition between β‐CD and adamantane‐modified guest polymers. In this system, β‐CD was first functionalized with two different polymer blocks, PEG and PDMAEMA, through a “click” reaction and ATRP. The guest polymer, composed of adamantane‐modified poly(methyl methacrylate) (PMMA), was then introduced to form the star‐shaped ABC terpolymer (Figure 4b).^{[ 96 ]} This amphiphilic terpolymer demonstrated the ability to self‐assemble into micelles in aqueous solution, with assembly and disassembly controlled by the addition of competitive host or guest molecules. The ABC miktoarm structure provided a versatile platform for creating responsive materials, as the micellar assemblies could be tuned for specific applications, such as drug delivery, by manipulating the host–guest interactions. This example highlights how CD‐based architecture can be tailored to form complex, multiblock systems with controlled assembly behaviors.

Figure 4.

Representative examples of CD‐based pseudo‐BCPs with star, dendrimer‐like, and hyperbranched architectures. a) β‐CD‐based miktoarm star polymers with PDMAAm and PDEAAm arms, synthesized via RAFT polymerization and azide–alkyne cycloaddition, exhibit stimulus‐responsive self‐assembly and disassembly triggered by temperature changes. Reproduced with permission.^{[ 95 ]} Copyright 2012, The Royal Society of Chemistry. b) Star‐shaped pseudo‐ABC terpolymers were constructed through host–guest interactions between β‐CD functionalized with PEG and PDMAEMA via click chemistry and ATRP and adamantane‐modified poly(methyl methacrylate) (PMMA) guest polymers. Reproduced with permission.^{[ 96 ]} Copyright 2012, American Chemical Society. c) A codelivery platform utilizing β‐CD‐PEI600 as the host and BM‐modified hyperbranched PCL (PCL–HPG–BM) as the guest to form the hyperbranched pseudocopolymer. Reproduced with permission.^{[ 97 ]} Copyright 2018, American Chemical Society.

Star polymers with a β‐CD core and polyacrylamide arms represent another class of supramolecular structures that utilize CD host–guest interactions. In this system, adamantyl‐functionalized chain transfer agents were used in the RAFT polymerization of N,N‐dimethylacrylamide and N,N‐diethylacrylamide, creating guest‐functionalized arms. These arms then interact with a β‐CD core through inclusion complexation to form three‐armed star‐shaped polymers.^{[ 98 ]} The self‐assembly behavior of these polymers has been extensively studied via techniques such as DLS and 2D ROESY, confirming their ability to form stable star architectures in solution. A key feature of this system is its thermoresponsive behavior, as demonstrated by changes in the LCST, which can be adjusted by altering the host–guest interactions. At elevated temperatures (70 °C), the star polymers disassembled, illustrating the reversible nature of the complexation and the potential for creating temperature‐responsive materials. Dendrimer‐like architecture provides another example of the versatility of CD‐based systems. In one study, supramolecular dendronized copolymers were constructed from a linear β‐CD‐containing polymer and second‐generation OEG dendritic guests.^{[ 99 ]} The host–guest interactions between β‐CD and the dendritic guests allowed the formation of dendronized polymers with tunable phase transition temperatures ranging from 34 to 56 °C. The supramolecular complexation process was investigated via ITC to determine the binding affinities, while proton NMR spectroscopy was used to study the dehydration and collapse of the OEG units. The more hydrophobic dendritic guests dissociated from the complex at lower temperatures, allowing precise control over the release of encapsulated materials. This dendrimer‐like architecture offers a high degree of structural control, making it suitable for drug delivery systems where temperature‐sensitive release is crucial.

Hyperbranched CD‐based architectures have also been developed for combined drug and gene delivery applications. In one representative system, the hyperbranched structure was constructed using oligoethylenimine‐conjugated β‐CD (β‐CD–PEI600) as the host and BM‐modified hyperbranched PCL (PCL–HPG–BM) as the guest (Figure 4c).^{[ 97 ]} The pH‐responsive inclusion assembly enhanced cellular uptake, gene transfection, serum stability, and biocompatibility, outperforming linear PEI‐based systems. Finally, a star‐shaped supramolecular copolymer system was developed for dual‐function applications in both diagnosis and treatment. The host polymer, PCL–β‐CD (4sPCL–CD), and the guest polymer, adamantylamine‐modified poly(l‐lactic acid)‐block‐poly(N‐isopropylacrylamide‐co‐2‐hydroxyethyl methacrylate) (AD–PLLA‐b‐P(NIPAAm‐co‐HEMA)), formed a star‐shaped copolymer that could self‐assemble into spherical micelles in aqueous solution.^{[ 100 ]} When chelated with gadolinium ions (Gd³⁺), the micelles acted as magnetic resonance imaging (MRI) contrast agents while also serving as carriers for controlled drug release. This dual functionality, combined with the temperature‐responsive behavior of the PNIPAAm chains, makes the system a promising candidate for simultaneous diagnostic imaging and targeted therapy.

4.4. Linear‐Star

The construction of a pseudo‐BCP with a linear–star architecture combines the benefits of both linear and star polymers, creating a versatile structure with unique advantages. The linear segments provide flexibility and facilitate interactions with other molecules, while the star segment offers a high density of functional sites and stability owing to its branched structure. This architecture enhances self‐assembly properties, allowing the formation of well‐defined nanostructures that can carry larger payloads than their purely linear counterparts. Additionally, the star segment can improve the overall stability of the assembly by reducing chain entanglement, while the combination of linear and star segments enables precise control over stimuli‐responsive behaviors. This makes linear–star pseudo‐BCPs particularly promising for applications in drug delivery and nanomedicine, where stability, responsiveness, and high loading capacity are essential.

One example involves a pseudo‐BCP based on organophosphazene polymers linked through supramolecular host–guest interactions. Here, a polyphosphazene host polymer with β‐CD moieties on its side chains interacted noncovalently with an adamantane end‐functionalized polyphosphazene guest, forming an amphiphilic, palm‐tree‐like assembly.^{[ 88 ]} This noncovalent linkage facilitated the formation of supramolecular structures with tunable aggregation and self‐assembly properties, as demonstrated by their ability to form gels and exhibit stimulus‐responsive behaviors. This modular approach to polyphosphazene modification highlights the adaptability of the linear–star structure for applications in responsive materials. Another study utilized β‐CD‐terminated star polymers of poly(N‐vinylpyrrolidone) (PVP) with either four or seven arms, which interacted with an adamantane‐terminated linear PCL to form supramolecular micelles (Figure 5a).^{[ 101 ]} The star‐shaped PVP arms served as the micellar exterior, reducing protein adsorption and improving stability, while the hydrophobic PCL core enabled high drug‐loading efficiency, achieving 85% encapsulation efficiency for the anticancer drug cabazitaxel. These micelles exhibited enhanced cytotoxicity against drug‐resistant cancer cell lines and significantly improved drug accumulation in tumor tissues, demonstrating the potential of the linear–star architecture for overcoming drug delivery challenges in cancer treatment.

Figure 5.

Representative examples of CD‐based pseudo‐BCPs with a linear–star architecture. a) β‐CD‐terminated star‐shaped poly(N‐vinylpyrrolidone) (PVP) polymers, which interact with adamantane‐terminated linear PCL, form stable supramolecular micelles with reduced protein adsorption and high drug‐loading efficiency. Reproduced with permission.^{[ 101 ]} Copyright 2015, The Royal Society of Chemistry. b) A β‐CD core with six poly(ethylene oxide) (PEO) arms was coupled with adamantyl‐terminated PNIPAAm to form temperature‐responsive “dumbbell” assemblies, which exhibited reversible phase transitions above 32 °C that triggered PNIPAAm aggregation and partial β‐CD host release. Reproduced with permission.^{[ 102 ]} Copyright 2015, The Royal Society of Chemistry. c) A pseudo‐BCP micellar system combining β‐CD‐based star PNIPAAm and Ad–PEG to form thermoresponsive micelles with high DOX‐loading capacity. Reproduced with permission.^{[ 103 ]} Copyright 2017, Elsevier B.V. d) A pseudo‐BCP with a linear–star architecture was developed from β‐CD‐based star PNIPAAm and BM‐modified PCL. The system formed stable micelles with high DOX‐loading capacity, enabling pH‐ and temperature‐triggered drug release. Reproduced with permission.^{[ 104 ]} Copyright 2018, Elsevier B.V. e) A redox‐sensitive β‐CD‐based PDMAEMA star polymer with disulfide bonds and zwitterionic phosphorylcholine groups enhanced gene transfection by improving cellular uptake and extracellular stability, offering a multifunctional platform for gene therapy. Reproduced with permission.^{[ 105 ]} Copyright 2014, Wiley‐VCH. f) A dual‐responsive system combining H₂O₂‐sensitive ferrocene‐modified PEG (Fc–mPEG) and β‐CD–PNIPAAm formed micelles with redox and thermal responsiveness, enabling precise drug release control. Reproduced with permission.^{[ 106 ]} Copyright 2021, Taylor & Francis Group. g) A cationic β‐CD‐based star polymer with PDMAEMA arms, complexed with mPEG–Ad, formed a pseudo‐BCP that demonstrated enhanced DNA condensation, low cytotoxicity, and improved transfection efficiency and stability, particularly with additional PEGylation for serum tolerance. Reproduced with permission.^{[ 107 ]} Copyright 2021, American Chemical Society.

In a similar approach, a β‐CD core bearing six poly(ethylene oxide) (PEO) arms was coupled with adamantyl‐terminated PNIPAAm to form temperature‐responsive “dumbbell” assemblies.^{[ 102 ]} At temperatures below 32 °C, the system formed stable inclusion complexes between the β‐CD and adamantane groups, while at higher temperatures, a reversible phase transition occurred, causing the PNIPAAm chains to aggregate and release a fraction of the β‐CD host (Figure 5b). This dual‐phase behavior, confirmed through NMR and calorimetry, illustrates the advantages of linear–star architectures in enabling temperature‐tunable properties for controlled release systems. Song et al. developed a pseudo‐BCP micellar system combining β‐CD‐based star PNIPAM and adamantane‐functionalized PEG (Ad–PEG) to form thermoresponsive micelles with a high drug‐loading capacity for DOX (Figure 5c).^{[ 103 ]} At body temperature, these micelles self‐assemble into stable nanoparticles, facilitating drug release within the hydrophobic core and maintaining biocompatibility. The inclusion complexation between β‐CD and adamantane enabled reversible assembly, demonstrating the utility of the linear–star architecture in creating stable yet responsive drug carriers with potential applications in cancer treatment. Further examples of dual‐responsive systems were developed using β‐CD‐based star polymers with PNIPAAm and BM‐modified PCL.^{[ 104 ]} The host β‐CD–PNIPAAm star and guest BM–PCL formed stable micelles with high drug‐loading capacity for DOX, which was released in response to changes in pH and temperature (Figure 5d). Another dual‐responsive system integrated H₂O₂‐responsive ferrocene‐modified PEG (Fc–mPEG) with β‐CD–PNIPAAm, producing micelles capable of dissociating in the presence of hydrogen peroxide (Figure 5f).^{[ 106 ]} The redox and thermal responsiveness offered precise control over drug release, showcasing the adaptability of linear–star assemblies for creating intelligent nanocarriers.

Gene delivery systems have also benefited from linear–star architectures. A cationic star‐shaped β‐CD‐based polymer with PDMAEMA arms was synthesized and complexed with mPEG–Ad via host–guest interactions (Figure 5g).^{[ 107 ]} This pseudo‐BCP exhibited superior DNA‐condensing ability, low cytotoxicity, and increased transfection efficiency in various cell lines, especially when further PEGylated to improve stability and serum tolerance. Additionally, a redox‐sensitive β‐CD‐based PDMAEMA star polymer functionalized with disulfide bonds enhanced gene transfection by incorporating zwitterionic phosphorylcholine groups that promoted cellular uptake and extracellular stability, providing an efficient, multifunctional system for gene therapy applications (Figure 5e).^{[ 105 ]}

4.5. Star–Star

A pseudo‐BCP with a star–star architecture combines the high functional density, stability, and structural versatility of two star‐shaped polymers, resulting in a robust and adaptable assembly with unique advantages. The multiarm design of both star components offers abundant sites for functionalization, enhancing the copolymer's capacity for high payloads, targeted delivery, or multifunctional responsiveness. This dual‐star structure allows for sophisticated self‐assembly, forming stable, well‐defined nanostructures that are often more resilient than linear–star or purely linear assemblies. Additionally, star–star copolymers can incorporate distinct stimuli‐responsive segments on each star, enabling precisely tuned responses to environmental triggers such as pH, temperature, or redox conditions.

One example of a multiresponsive star–star architecture is the amphiphilic supramolecular polymer β‐CD–(PNIPAAm)₄–Azo–(PMAA)₇, where β‐CD is the core of one star connected to four PNIPAAm arms, while an azobenzene‐modified poly(methacrylic acid) (PMAA) forms the other star segment.^{[ 110 ]} The host–guest interaction between β‐CD and azobenzene links the stars, enabling the system to respond to multiple stimuli. In water, this polymer self‐assembles into inverse spherical nanoaggregates and can reversibly disassemble when exposed to UV light, as azobenzene undergoes trans‐to‐cis isomerization. The structure can also undergo pH‐ and temperature‐driven assembly and disassembly, as demonstrated through DLS and transmission electron microscopy studies. This tunable responsiveness makes β‐CD–(PNIPAAm)₄–Azo–(PMAA)₇ ideal for smart material applications where structural adjustments can be triggered by environmental changes.

Another star–star system explored the potential for creating stable unimolecular micelles from supramolecular star copolymers. A panel of 9‐, 12‐, and 18‐arm star‐shaped BCPs was constructed through the complexation of Fc‐terminated PCL stars with β‐CD‐functionalized POEGMA stars.^{[ 111 ]} The synthesis involved ROP of PCL stars with 3, 4, or 6 arms capped with Fc and ATRP‐produced POEGMA stars initiated by β‐CD. The resulting star–star pseudo‐BCPs exhibited stability and responsiveness, particularly the 12‐arm star structure, which showed optimal stability in micellar form and reactive‐oxygen‐species (ROS)‐triggered drug release due to the oxidation‐sensitive β‐CD/Fc linkage. The 12‐arm configuration proved effective for drug delivery, balancing stability and therapeutic efficacy while retaining high colloidal stability and responsiveness under biological conditions. In an intriguing example, polyrotaxanes (PRs) are formed from star‐shaped PCL as the axle and pillar[5]arene as the wheel, with β‐CD serving as a host for pH‐sensitive PAA (Figure 6a).^{[ 108 ]} This design enables vesicle formation with well‐defined structure and responsiveness, showcasing the versatility of supramolecular assemblies with a star–star architecture.

Figure 6.

Representative examples of CD‐based pseudo‐BCPs with a star–star architecture. a) Polyrotaxanes formed from star‐shaped PCL, pillar[5]arene, and β‐CD‐hosted pH‐sensitive PAA self‐assembled into vesicular nanoparticles with exceptional drug‐loading capacity and pH‐responsive release. Reproduced with permission.^{[ 108 ]} Copyright 2018, American Chemical Society. b) A thermoresponsive star–star hydrogel was created by inclusion complexation between an adamantyl‐terminated 8‐arm PEG star and a β‐CD‐cored PNIPAAm star, forming a reversible 3D network sensitive to temperature changes. Reproduced with permission.^{[ 109 ]} Copyright 2013, Wiley‐VCH.

In a diagnostic context, star–star supramolecular vesicles were formed by assembling PR–PAA with hydrophobic magnetite nanoparticles, followed by cross‐linking with organosilica and PEG modification.^{[ 112 ]} The resulting PEGylated hybrid vesicles exhibited tunable morphologies and, at optimal Fe₃O₄ loading (3.0 mg mL⁻¹), formed sub‐100 nm vesicles with high colloidal stability and strong T₂ relaxivity. Finally, a temperature‐responsive star–star hydrogel was assembled from an adamantyl‐terminated 8‐arm PEG star and a β‐CD‐cored PNIPAAm star.^{[ 109 ]} Through inclusion complexation, these star‐shaped components formed a thermoresponsive 3D hydrogel network that could reversibly assemble and disassemble in response to temperature (Figure 6b). This “smart” hydrogel demonstrates the unique advantage of star–star architecture in creating reversible, stimuli‐responsive soft materials suitable for applications in tissue engineering, drug delivery, and responsive biomaterials.

4.6. Other Interesting Architectures

The field of supramolecular host–guest chemistry has enabled the development of “interesting architectures” with innovative features that harness the unique properties of host–guest interactions. These architectures facilitate the design of systems with controlled assembly, responsiveness to environmental stimuli, and enhanced functionalities. Here, we explore several notable examples of diverse applications, including gene delivery, drug delivery, responsive hydrogels, and advanced conductive materials.

One such architecture involves CS‐graft‐(PEI–β‐CD) (CPC) cationic copolymers, which are synthesized by grafting β‐CD‐PEI onto oxidized CS (Figure 7a).^{[ 113 ]} This modular design enables stable nanoparticle formation and allows supramolecular PEGylation via host–guest interactions, showcasing the structural adaptability of CPC systems for tailored nucleic acid delivery. Another architecture featuring a “jellyfish‐like” structure was developed with β‐CD–PCL.^{[ 114 ]} Here, flexible, hydrophobic PCL arms were grafted onto the wide side of the torus‐shaped β‐CD, creating an amphiphilic polymer. This structure self‐assembled into vesicles in water, while further complexation with Fc‐functionalized PEG (FcPEG) enabled the formation of nanospheres (Figure 7b). The resulting β‐CD–PCL/FcPEG supramolecular nanospheres exhibited significant structural stability, although the embedded ferrocenyl groups were restricted from undergoing redox reactions, revealing how supramolecular complexation can limit or enhance specific functionalities, depending on the desired application.

Figure 7.

Unique supramolecular architectures of CD‐based pseudo‐BCPs. a) A CS‐graft‐(PEI–β‐CD) (CPC) cationic pseudocopolymer synthesized by grafting β‐CD–PEI onto oxidized CS effectively condenses pDNA and siRNA into stable nanoparticles, offering superior gene transfection efficiency, lower cytotoxicity than PEI, and enhanced stability through PEGylation via host–guest interactions. Reproduced with permission.^{[ 113 ]} Copyright 2011, Elsevier B.V. b) A “jellyfish‐like” architecture combining β‐CD–PCL and Fc‐functionalized PEG (FcPEG) self‐assembles into vesicles and nanospheres in water. Reproduced with permission.^{[ 114 ]} Copyright 2013, Elsevier B.V. c) A multifunctional redox‐sensitive delivery system, ROSE/microRNA‐34a (miR‐34a), self‐assembled from polycations and adamantyl modules with SP94‐guided targeting moieties. Reproduced with permission.^{[ 115 ]} Copyright 2016, Elsevier B.V. d) A redox‐sensitive PEG‐based gene vector targeting fibroblast growth factor receptor (FGFR) was constructed using β‐CD cross‐linked PEI and disulfide‐bonded PEG, forming a supramolecular complex with pDNA for efficient, targeted delivery. Reproduced with permission.^{[ 116 ]} Copyright 2013, Elsevier B.V. e) Poly(β‐CD)‐based supramolecular systems were created by complexing β‐CD with adamantyl‐terminated PEI and PEG, forming stable, PEGylated polyplexes for pDNA delivery with improved stability and efficiency. Reproduced with permission.^{[ 117 ]} Copyright 2016, American Chemical Society. f) A biodegradable nanocomplex combining β‐CD‐grafted hyaluronic acid (HA) and phenylalanine‐based poly(ester amide) enabled CD44‐targeted delivery and the enzymatic release of gambogic acid. Reproduced with permission.^{[ 118 ]} Copyright 2017, Elsevier B.V. g) Host–guest complexation between bridged β‐CD and functional acrylamide polymers resulted in supramolecular systems with increased viscosity, salt tolerance, shear resistance, and thermoresponsiveness. Reproduced with permission.^{[ 119 ]} Copyright 2016, The Royal Society of Chemistry. h) A dual‐network, temperature‐responsive hydrogel was developed by self‐assembling β‐CD‐cored PNIPAAm with adamantyl‐terminated PEG and α‐CD, forming injectable pseudorotaxane hydrogels capable of temperature‐triggered DOX release. Reproduced with permission.^{[ 120 ]} Copyright 2020, American Chemical Society.

Moreover, a multifunctional delivery system was designed with a redox‐sensitive, oligopeptide‐guided polymer that enhances the gene transfection efficiency of ROSE/microRNA‐34a (miR‐34a) in hepatocellular carcinoma (HCC) cells.^{[ 115 ]} This system uses polycations and functional adamantyl modules to self‐assemble with miR‐34a, a tumor‐suppressor microRNA, to form nanoparticles that demonstrate high stability, selective targeting, and redox‐responsive release (Figure 7c). The system's targeting oligopeptide, SP94, facilitated specific binding to HCC cells, and the nanoparticles significantly inhibited tumor growth in vitro and in vivo. This redox‐sensitive, self‐assembling polymer has potential for use in advanced supramolecular systems to increase gene delivery efficacy for cancer therapy. In another example, PCD‐based supramolecular systems were developed by complexing β‐CD with adamantyl‐terminated PEI and PEG.^{[ 117 ]} PCD is assembled with low‐molecular‐weight PEI to form stable polyplexes for pDNA, which can be PEGylated for enhanced stability (Figure 7e). These polyplexes demonstrated good cytocompatibility, high transfection efficiency, and moderate siRNA‐mediated silencing, indicating that this host–guest system is effective as a versatile gene delivery vector with strong therapeutic potential.

A notable architecture is a redox‐sensitive PEG‐based gene vector designed for fibroblast‐growth‐factor‐receptor (FGFR)‐mediated targeting.^{[ 116 ]} This system uses β‐CD cross‐linked with PEI and a PEG chain linked by a disulfide bond to form a supramolecular complex with pDNA (Figure 7d). The PEGylated polyplex demonstrated strong stability against salt and serum, as well as efficient intracellular release and endosomal escape, which was attributed to cleavable disulfide bonds. This FGFR‐targeted, redox‐responsive system highlights how supramolecular engineering can produce vectors with tailored targeting and release properties for specific cancer therapies. For targeted chemotherapy, a biodegradable nanocomplex based on β‐CD‐grafted hyaluronic acid (HA) and phenylalanine‐based poly(ester amide) was developed to enhance the delivery and efficacy of gambogic acid, a chemotherapeutic agent (Figure 7f).^{[ 118 ]} The HA component enables targeted delivery to tumor cells overexpressing CD44 receptors, and enzymatic degradation facilitates gambogic acid release, enhancing its cytotoxic effects in multidrug‐resistant cancer cells. This nanocomplex has the advantages of combining biodegradable components with targeted delivery capabilities in supramolecular systems, significantly increasing drug solubility, stability, and therapeutic efficacy.

Another interesting architecture involves host–guest complexation between bridged β‐CD and functional acrylamide polymers (Figure 7g).^{[ 119 ]} The resulting supramolecular polymeric systems exhibited enhanced properties such as improved viscosity, salt tolerance, shear resistance, and thermoresponsiveness. These characteristics suggest potential applications in fields requiring robust, adaptable materials, including biomedicine and environmental science, as the host–guest system strengthens the mechanical and environmental resilience of acrylamide‐based polymers. A dual‐network, temperature‐responsive hydrogel with promising potential for drug delivery was created by self‐assembling β‐CD‐cored PNIPAAm with adamantyl‐terminated PEG as well as α‐CD to form an injectable pseudorotaxane hydrogel with PEG chains (Figure 7h).^{[ 120 ]} This thermoresponsive hydrogel formed micelles that encapsulated DOX, which was released in response to temperature increases. The hydrogel demonstrated sustained drug release and enhanced cellular uptake, particularly in multidrug‐resistant cancer cells, demonstrating the efficacy of CD‐based hydrogels for temperature‐controlled drug delivery.

4.7. Screening Platform

The host–guest block‐building strategy has become a powerful approach for constructing intricate supramolecular architectures with tunable properties, providing a simple, versatile, and modular platform for screening potential drug and gene delivery systems. By harnessing the noncovalent interactions between host and guest polymers, these systems enable rapid optimization of molecular architecture, making them ideal candidates for delivering therapeutics with controlled release, targeted delivery, and environmental responsiveness. This section reviews recent developments in host–guest supramolecular systems as screening platforms for advanced delivery applications, emphasizing the role of synthetic strategies and topological structures in achieving optimized self‐assembly, stability, and responsiveness.

One example of this strategy involves the synthesis of three distinct azobenzene‐terminated PEG guest polymers with varying end groups, PEG–azo, azo–PEG–azo, and PEG–azo₄. These guest polymers were coupled with β‐CD–PLLA, a star‐shaped host polymer, to form supramolecular amphiphiles with three distinct topologies: hemitelechelic, ditelechelic, and quadritelechelic.^{[ 121 ]} Self‐assembly studies revealed that the structure of the guest polymers significantly influenced the hydrophilic–hydrophobic balance and polymer chain curvature, allowing precise control over the morphology of self‐assembled structures. This structural control is valuable for tuning particle size and stability, providing a screening tool for delivery applications where specific nanoscale morphologies are desired. A similar approach has been applied to siRNA delivery. A β‐CD‐based cationic polymer, CD–SS–PDMAEMA, served as the host and was complexed with Ad–PEG guest polymers in both linear and comb‐like forms, some with folic acid ligands for targeted delivery. This modular assembly allowed the screening of various configurations and the optimization of shielded and targeted delivery for siRNA–Bcl2.^{[ 122 ]} This host–guest platform enables the precise tuning of siRNA carrier properties, allowing efficient delivery of the siRNA–Bcl2 complex with high tumor targeting ability and low nonspecific uptake. This modular approach, which offers fast optimization and high adaptability, illustrates the utility of host–guest systems as screening tools for gene delivery vehicles.

A thermosensitive core‐cross‐linked star polymer, β‐CD–PNIPAAm, was synthesized via ATRP to form a responsive micelle system.^{[ 123 ]} By varying the concentrations of the cross‐linker N,N‐methylenebisacrylamide, researchers synthesized PNIPAAm stars with 47, 86, and 211 arms, which were then functionalized with β‐CD to enable guest complexation with adamantyl‐terminated poly(4‐vinylpyridine) (Ad–P4VP). This approach generated a thermoresponsive star polymer with both pH and temperature sensitivity, allowing it to form stable micellar structures. This screening platform allows for rapid testing of different cross‐linking densities and arm configurations to optimize drug release properties for applications requiring dual responsiveness. In another temperature‐responsive system, star‐shaped PNIPAAm with a β‐CD core was used as the host polymer, while bis(adamantyl)‐terminated poly(propylene glycol) (PPG) served as the guest polymer.^{[ 124 ]} This host–guest system exhibited dual thermoresponsiveness due to the PNIPAAm and PPG components, which underwent a reversible transition from micelles to aggregates with temperature changes. The critical micelle temperature can be finely tuned by adjusting the host–guest ratio, making it suitable for creating a screening platform for temperature‐sensitive delivery systems where precise control over self‐assembly is essential. Light‐responsive supramolecular polymer brushes provide another flexible platform.^{[ 90 ]} These brushes were created through the host–guest interaction between the β‐CD and azobenzene groups, resulting in structures that could be tuned from unimolecular micelles to vesicles and larger superstructures by altering the ratio of host and guest polymers. The azobenzene component allows UV‐triggered disassembly, making this platform suitable for screening drug delivery vehicles that require controlled release in response to external light stimuli. This system demonstrated adjustable sizes from 28 to 300 nm, offering a versatile range for optimizing therapeutic nanoparticle sizes.

These examples illustrate how host–guest block‐building strategies can serve as effective screening platforms for the rapid optimization of drug and gene delivery vehicles. By tuning their molecular structure, responsiveness, and self‐assembly characteristics, these platforms enable precise control over release profiles, targeting capabilities, and biocompatibility, highlighting their valuable role in advancing therapeutic delivery systems.

5. Biomedical Applications of Cyclodextrin‐Based Pseudocopolymers

5.1. Drug Delivery

Many therapeutic agents suffer from poor water solubility and low bioavailability, making it difficult for them to be absorbed effectively into the bloodstream or cells. Drug delivery systems address these limitations by improving these properties, enhancing the drug's efficacy at lower doses, and directing it to target sites within the body. However, these systems face complex challenges, primarily due to the intricacies of the biological environment and the need for precise targeting to reduce side effects and maximize therapeutic benefits. Upon introduction into the body, drug carriers must navigate a variety of biological barriers, such as immune clearance and unintended interactions with nontarget cells. Effective drug carriers also need to release their therapeutic payload in a controlled manner at the intended site, which often demands responsiveness to specific stimuli, such as pH, temperature, or redox conditions. Given these challenges, pseudo‐BCPs created through host–guest interactions have emerged as valuable tools in drug delivery, offering structural flexibility, stimulus responsiveness, and enhanced biocompatibility. This section explores the diverse applications of pseudo‐BCPs in drug delivery, outlining their design, functionality, and in vivo performance.

One notable system utilizes pseudo‐BCP micelles based on β‐CD‐terminated star PVP and adamantane‐terminated linear PCL.^{[ 101 ]} By forming micelles with a 7‐armed PVP exterior, this system achieved high stability, minimized protein adsorption, and offered highly efficient loading of cabazitaxel, a potent yet challenging taxane drug. The drug‐loaded micelles demonstrated a loading content of 14.4% and an encapsulation efficiency of 85%, indicating robust drug‐carrying capability. In cytotoxicity studies on drug‐resistant A2780/T ovarian cancer cells, cabazitaxel‐loaded micelles induced significant cell death, reflecting their potential to overcome multidrug resistance. Biodistribution studies further revealed that the micelles enabled nearly double the accumulation of cabazitaxel at tumor sites compared with free drug formulations. These findings were corroborated by in vivo antitumor activity assays, where the micelle‐encapsulated drug outperformed free cabazitaxel and even paclitaxel, highlighting the system's potential as a highly effective carrier for chemotherapeutics. In another innovative approach, photocontrolled host–guest interactions between azobenzene and β‐CD were harnessed to create poly((itaconoyloxy)ethyl methacrylate)‐block‐poly(N‐isopropylacrylamide) hollow nanospheres.^{[ 85 ]} This strategy allows precise control over drug release through phototriggered responses, which facilitates the efficient release of encapsulated DOX upon exposure to light. These hollow nanospheres exhibit “breathing” behavior, expanding and contracting in response to environmental stimuli, which optimizes DOX release in targeted areas. Cellular studies confirmed that the nanospheres possess excellent biocompatibility, making them viable candidates for targeted cancer therapies that benefit from localized, on‐demand drug release.

pH‐responsive supramolecular micelles have also been developed using PEG–BM and β‐CD–PLLA, which target acidic tumor environments (Figure 8a).^{[ 82 ]} These micelles, which are designed to release DOX under acidic conditions, capitalize on the host–guest interaction between the BM and β‐CD. In vitro studies revealed accelerated DOX release in HepG2 cells at pH levels mimicking the tumor microenvironment, while in vivo studies revealed significant tumor inhibition and reduced systemic toxicity. Pharmacokinetics revealed that these micelles exhibit longer circulation time than free DOX does, demonstrating their ability for sustained delivery. Owing to their pH‐responsive properties and enhanced pharmacokinetics, PEG–BM/β‐CD–PLLA micelles are promising nanocarriers for precise and efficient cancer drug delivery. A pseudo‐BCP using β‐CD‐terminated poly(N‐acryloylmorpholine) and adamantane‐terminated linear poly(d,l‐lactide) was created for pH‐sensitive drug delivery.^{[ 128 ]} DOX was effectively loaded into these micelles, and studies demonstrated accelerated drug release under acidic conditions, mimicking the tumor environment. This pH‐triggered release characteristic showed the system's suitability for applications requiring enhanced drug delivery specificity, providing significant promise for treating cancers that exhibit a more acidic microenvironment. Additionally, dual pH‐sensitive supramolecular micelles were developed from β‐CD–(PDMAEMA)₇, a star polymer of PDMAEMA with β‐CD cores, and BM‐modified PCL as the guest.^{[ 129 ]} The micelles, with a hydrophobic core of β‐CD/BM–PCL and a pH‐sensitive PDMAEMA shell, showed a high loading capacity and entrapment efficiency for DOX, up to 40% and 86%, respectively. Compared with free DOX, the micelles accelerated DOX release at lower pH values and higher temperatures, with in vitro assays showing greater cancer cell inhibition. These properties suggest that these micelles are promising smart and targeted drug delivery systems relevant to acidic and heated environments, such as tumor tissues. Moreover, a PR–PAA‐based supramolecular vesicular nanoparticle system formed from pillar[5]arene polyrotaxane and β‐CD–PAA demonstrated an impressive drug‐loading capacity of 45.6% for DOX, which was attributed to the reduced crystallinity of PCL in the PR.^{[ 108 ]} While the original study emphasized the amorphization of PCL as the primary mechanism for enhanced drug encapsulation, it is also plausible that π–π interactions between the aromatic rings of pillar[5]arene and DOX contributed synergistically to the overall drug‐loading efficiency, particularly given the known affinity of anthracycline compounds for aromatic macrocycles. The vesicles released DOX under acidic conditions, simulating tumor environments, and displayed enhanced cellular uptake and cytotoxicity against cancer cells. In vivo studies further revealed efficient accumulation at tumor sites, highlighting the system's potential as a high‐capacity drug carrier with tumor‐targeting capabilities. In another study, a well‐defined pH‐sensitive system based on [PHEMA‐g‐(PCL–BM):β‐CD‐star‐(PDMAEMA)₇] was synthesized via host–guest interactions to form self‐assembled nanomicelles for the administration of hydrophobic drugs.^{[ 130 ]} These micelles, with an average size of ≈97.1 nm, effectively encapsulate docetaxel with an efficiency of 82%. Biocompatibility assessments of MCF‐7 breast cancer cells confirmed their suitability for cancer therapy, and cellular uptake studies revealed efficient internalization, suggesting that this system is a potential candidate for cancer treatment.

Figure 8.

Representative examples of CD‐based pseudo‐BCPs used as advanced drug delivery systems. a) pH‐responsive PEG–BM/CD–PLLA micelles, formed through host–guest interactions between BMs and β‐CD, demonstrated accelerated DOX release in acidic tumor environments, significant tumor inhibition, reduced systemic toxicity, and prolonged circulation time. Reproduced with permission.^{[ 82 ]} Copyright 2015, American Chemical Society. b) A set of star‐shaped amphiphilic pseudocopolymers synthesized via host–guest complexation between Fc‐capped PCL and β‐CD‐cored POEGMA demonstrated stability and ROS‐triggered DOX release, effectively targeting oxidative tumor microenvironments. Reproduced with permission.^{[ 111 ]} Copyright 2018, Elsevier B.V. c) A cisplatin‐loaded supramolecular pseudo‐BCP, which combines β‐CD‐capped PVP and adamantane‐capped poly(aspartic acid), achieved high drug‐loading efficiency (≈50%), pH stability, Cl⁻‐induced disintegration, and superior in vivo antitumor efficacy with enhanced tumor accumulation and improved survival outcomes compared with free cisplatin. Reproduced with permission.^{[ 125 ]} Copyright 2015, American Chemical Society. d) A glutathione (GSH)‐responsive graft copolymer system was developed by combining β‐CD–PEI and 5,5′‐dithiobis‐(2‐nitrobenzoic acid) (DTNB)‐modified dextran to form nanoparticles that encapsulate lonidamine (LND), delivering it to cancer cells while depleting GSH, inducing ROS generation, mitochondrial dysfunction, and immunogenic cell death, with TNB2⁻ release and enabling real‐time GSH monitoring. Reproduced with permission.^{[ 126 ]} Copyright 2023, Elsevier B.V. e) A multifunctional nanoplatform (TPL/PBAETK@GA NPs) targeting hepatocellular carcinoma utilized glycyrrhetinic‐acid‐modified PEG–adamantane carboxylic acid and a ROS/pH‐responsive poly(β‐amino esters)–thioketal (TK)–β‐CD copolymer to achieve tumor‐specific accumulation, ROS‐triggered layer detachment, charge reversal, and pH‐sensitive burst release of triptolide, leading to enhanced cellular internalization, apoptosis, autophagy, and a self‐amplifying ROS feedback loop. Reproduced with permission.^{[ 127 ]} Copyright 2024, American Chemical Society.

In another study, a set of star‐shaped amphiphilic copolymers with 9, 12, and 18 arms was synthesized through host–guest complexation between PCL–Fc and β‐CD‐cored POEGMA (Figure 8b).^{[ 111 ]} Among the configurations, the 12‐arm copolymer demonstrated optimal stability and ROS‐triggered DOX release, making it effective for targeting oxidative tumor microenvironments. Cytotoxicity studies have shown that the 12‐arm configuration maintains a balance between stability and therapeutic efficacy, providing an excellent example of how the degree of branching can be fine‐tuned for drug delivery. A cisplatin‐loaded supramolecular pseudo‐BCP was developed using β‐CD‐capped PVP and adamantane‐capped poly(aspartic acid), followed by the coordination of cisplatin to the carboxyl groups on poly(aspartic acid) (Figure 8c).^{[ 125 ]} The resulting nanoparticles displayed high drug loading efficiency (≈50%) and stability across various pH conditions while remaining susceptible to Cl⁻‐ion‐induced disintegration, which is ideal for tumor microenvironments. The nanoparticles were further tested in vivo, where they demonstrated increased accumulation at the tumor site due to their favorable pharmacokinetic profile. Additionally, they showed improved antitumor efficacy compared with free cisplatin, as evidenced by tumor volume reduction, weight maintenance, and extended survival in animal models. This study demonstrated the potential of such nanoparticles in enhancing the therapeutic index of cisplatin.

A supramolecular micellar system was also engineered from CS oligosaccharide₂₅₀₀–β‐CD–PLA₃₀₀₀, which uses H‐bonding‐directed double disulfide linkages and host–guest complexation between β‐CD and adamantane.^{[ 131 ]} These micelles showed stability under physiological conditions and controlled redox‐responsive release of DOX, indicating their effectiveness in HeLa cell line studies. Owing to its ability to trigger drug release via redox sensitivity, this platform offers an innovative solution for targeting tumor cells where oxidative stress is often high. Furthermore, Tang et al. developed a responsive graft copolymer system designed for anticancer drug delivery. The system utilized β‐CD–PEI as the host polymer and a dextran‐based guest polymer modified with 5,5′‐dithiobis‐(2‐nitrobenzoic acid) (DTNB) (Figure 8d).^{[ 126 ]} This combination enabled the formation of glutathione (GSH)‐responsive nanoparticles that effectively encapsulated lonidamine (LND), an inhibitor of mitochondrial function, within the core. In addition to delivering LND, the nanoparticles facilitated the depletion of GSH in the cancer cells, enhancing therapeutic efficacy. This dual‐function delivery system not only controlled drug release under GSH‐rich conditions typical of the tumor microenvironment but also released TNB2⁻ as a probe for in situ GSH detection, allowing real‐time monitoring of cellular responses. This system induces high ROS levels, contributing to mitochondrial dysfunction and promoting immunogenic cell death in cancer cells. In a similar vein, a multifunctional supramolecular nanoplatform loaded with triptolide (TPL/PBAETK@GA NPs) was developed, drawing on the host–guest interaction between glycyrrhetinic‐acid‐modified PEG–adamantane carboxylic acid and a ROS/pH‐responsive copolymer, poly(β‐amino esters)–thioketal (TK)–β‐CD (Figure 8e).^{[ 127 ]} This system targets HCC by utilizing glycyrrhetinic acid (to recognize specific receptors and accumulate effectively in tumor tissue. Upon encountering elevated ROS in the tumor microenvironment, the TK linkages break, causing detachment of the CD layer and triggering negative‐to‐positive charge reversal via PBAE protonation under acidic conditions, enhancing cellular internalization. The pH‐sensitive PBAE core then enables endo/lysosomal escape and burst release of TPL, driving apoptosis, autophagy, and intracellular ROS generation to create a self‐amplifying ROS feedback loop. In vitro and in vivo studies verified that the TPL/PBAETK@GA NPs achieved notable anti‐HCC outcomes. Overall, this study provides an innovative framework for enhancing TPL‐based therapies through multifunctionalized supramolecular nanodrugs, offering a promising approach to overcoming challenges in cancer drug delivery.

To address the challenges of multidrug resistance, a biodegradable HA(CD)–4Phe4 nanocomplex was created using β‐CD‐grafted HA combined with a phenylalanine‐based poly(ester amide).^{[ 118 ]} This design aimed to increase the solubility and bioavailability of GA, a chemotherapeutic limited by low water solubility and nonselective toxicity. In the presence of hyaluronidase, the GA‐loaded nanocomplexes displayed accelerated drug release, leveraging enzyme‐responsive behavior for improved targeting of CD44‐overexpressing tumor cells. Compared with free GA, the nanocomplexes exhibited increased cytotoxicity and apoptosis in multidrug‐resistant MDA‐MB‐435/MDR melanoma cells, increased mitochondrial depolarization, and significantly reduced matrix metalloproteinase activity, which is implicated in tumor metastasis. To further capitalize on HA's CD44‐targeting properties and biocompatibility, a new system integrating tumor‐microenvironment‐responsive mechanisms was developed using a cross‐linkable diethoxysilyl unit.^{[ 132 ]} This innovation allowed in situ cross‐linking without additives, addressing issues of batch variation and complex preparation associated with HA‐based multicomponent nanomedicines. The system employed HA–β‐CD and Fc‐functionalized polymers, Fc–POEGMA and Fc‐terminated PCL‐b‐poly(3‐(diethoxymethylsilyl)propyl(2‐(methacryloyloxy)ethyl) carbamate) to create ROS‐sensitive supramolecular amphiphilic copolymers. This design generated core‐cross‐linked micelles that maintained extracellular colloidal stability and facilitated ROS‐induced aggregation within CD44‐positive HeLa cells, enhancing the intracellular release of the loaded drugs. Importantly, these micelles displayed greater cytotoxicity in CD44 receptor‐positive cells than in receptor‐negative cells, illustrating their potential for selective anticancer therapy. Together, these approaches highlight the versatility of HA‐based nanocomplexes for efficient, targeted drug delivery in cancer treatment.

Overall, these diverse applications accentuate the adaptability and efficacy of pseudo‐BCPs in addressing the complex challenges of drug delivery. By enabling precise control over macromolecular architecture and stimuli responsiveness, these supramolecular systems offer versatile and reliable solutions for targeted and controlled drug release.

5.2. Gene Delivery

Gene delivery is a complex and challenging process because multiple biological barriers restrict the efficient transport and release of genetic material into target cells. Upon administration, gene delivery systems encounter extracellular barriers such as enzymatic degradation, immune system recognition, and rapid clearance. Intracellularly, they face further challenges, including cell membrane crossing, endosomal escape, and precise release within the target cell's nucleus. Moreover, safety concerns related to cytotoxicity and off‐target effects add additional constraints on effective gene carrier design. To address these challenges, pseudo‐BCPs utilizing host–guest chemistry have emerged as an innovative and flexible approach. These systems enable the formation of multifunctional gene carriers with tunable properties, allowing for modular adaptation to overcome each specific barrier. This section delves into various examples of pseudo‐BCP‐based gene delivery systems, with emphasis on their synthesis, host–guest interactions, and application‐specific results.

One notable example involves a supramolecular comb‐like polycation system synthesized through the interaction of adamantane‐modified poly(glycidyl methacrylate) (PGEA) with a β‐CD‐cored PGEA star polymer (Figure 9a).^{[ 133 ]} This system forms comb‐like pseudocopolymer structures with enhanced pDNA‐condensing ability and reduced cytotoxicity, significantly improving the transfection efficiency in the HepG2 and HEK293 cell lines compared with their non‐comb‐like counterparts. The noncovalent host–guest interaction not only provides structural flexibility but also facilitates tuning of the polymer's functionality, demonstrating the potential of supramolecular comb‐like polycations as gene carriers. The ROSE platform exemplifies another application of pseudo‐BCPs in gene delivery, which targets HCC.^{[ 115 ]} Constructed from a polycationic core and functional adamantyl modules, the ROSE system condenses tumor suppressor miR‐34a into nanoparticles. This redox‐sensitive, self‐assembled system features oligopeptide‐guided targeting, enhanced stability via PEGylation, and controlled release facilitated by disulfide bond cleavage in the tumor microenvironment. In vitro and in vivo studies have shown that ROSE/miR‐34a nanoparticles effectively inhibit HCC cell proliferation and tumor growth, suggesting a promising approach for gene‐based adjuvant therapy in HCC. In another approach addressing hard‐to‐reach targets, a linear–star pseudo‐BCP was developed by assembling adamantyl‐terminated PEG–poly[(R,S)‐β‐hydroxybutyrate] guest polymers with a cationic four‐arm β‐CD–pDMAEMA host polymer.^{[ 135 ]} This amphiphilic supramolecular system formed stable DNA micelleplex nanoparticles with tunable block composition, low cytotoxicity, and high transfection efficiency. Subsequent surface modification with apolipoprotein E3 endowed the nanoparticles with blood–brain‐barrier (BBB)‐penetrating capability, as confirmed by an in vitro BBB transwell model. This study exemplifies how topologically engineered pseudo‐BCPs, guided by host–guest interactions, can be systematically optimized for central‐nervous‐system‐targeted gene delivery.

Figure 9.

Representative examples of CD‐based pseudo‐BCPs designed to overcome gene delivery challenges. a) A supramolecular comb‐like polycation system (l‐PGEA–Ad/CD–PGEAs) formed from adamantane‐modified and β‐CD‐cored poly(glycidyl methacrylate) exhibited superior plasmid DNA‐condensing ability, reduced cytotoxicity, and significantly enhanced transfection efficiency in HepG2 and HEK293 cell lines compared to non‐comb‐like systems. Reproduced with permission.^{[ 133 ]} Copyright 2013, American Chemical Society. b) A modular supramolecular gene delivery system, which combines a β‐CD‐based star polymer (poly(β‐CD) (PCD)–SS–PDMAEMA) with disulfide‐linked arms and an adamantyl and folate‐terminated PEG (Ad–PEG–FA) guest polymer, forms stable nanosized polyplexes with folate‐receptor specificity, excellent biocompatibility, high transfection efficiency for pDNA and siRNA, and reductive environment‐triggered DNA release. Reproduced with permission.^{[ 92 ]} Copyright 2016, American Chemical Society. c) A supramolecular screening platform based on a host β‐CD with bioreducible disulfide‐linked PDMAEMA arms (CD–SS–PDMAEMA) and adamantyl‐functionalized PEG (Ad–PEG) guest polymers in various architectures and folate functionalization, enabling efficient siRNA delivery and targeted gene therapy with high specificity in vitro and in vivo. Reproduced with permission.^{[ 122 ]} Copyright 2020, American Association for the Advancement of Science. d) A multifunctional gene delivery system combining PCD, a redox‐sensitive rhodamine‐tagged azobenzene branched polymer (Az–ss–BPDM–RhB), and adamantyl‐terminated folate‐modified PEG (Ad–PEG–FA) offers fluorescence traceability, enhanced cell uptake, and targeted delivery. Reproduced with permission.^{[ 134 ]} Copyright 2016, American Chemical Society.

A modular approach for multifunctional gene delivery utilizes a supramolecular assembly of a PCD–SS–PDMAEMA and an Ad–PEG–FA guest polymer (Figure 9b).^{[ 92 ]} This PCD–SS–PDMAEMA/PEG–FA complex compacts DNA into stable nanosized polyplexes with targeted folate receptor specificity, excellent biocompatibility, and high transfection efficiency for both pDNA and siRNA. The system's design allows specific pDNA release in reductive environments, making it a flexible and efficient platform for targeted gene therapy and demonstrating the effectiveness of modular approaches in constructing adaptable, multifunctional gene carriers. Similarly, Wen et al. developed a supramolecular platform using a β‐CD‐based cationic host polymer, β‐CD–SS–PDMAEMA, which links PDMAEMA arms to a β‐CD core through bioreducible disulfide bonds (Figure 9c).^{[ 122 ]} This host polymer condenses siRNA and facilitates its release in a reductive environment, forming polyplex nanoparticles with guest polymers such as Ad–PEG, which are tailored in various architectures (linear and comb‐like) with folic acid for targeted delivery. The in vitro and in vivo results revealed efficient siRNA delivery and high targeting specificity, emphasizing the modularity and efficacy of host–guest systems in gene delivery optimization. Another supramolecular gene delivery system utilizes PEI–Ad and PEG, which are assembled with PCD through host–guest complexation.^{[ 117 ]} This system condenses DNA via electrostatic interactions, forming polyplexes with PEGylated surfaces for improved salt and serum stability. Testing revealed that the PEI–Ad/PCD complexes offer high transfection activity and good cytocompatibility, providing a versatile platform for gene delivery applications. This design demonstrated that host–guest interactions in pseudo‐BCP architectures enable stable and efficient gene carriers with reduced cytotoxicity.

In a different approach, CPC copolymers were synthesized as cationic carriers that condense pDNA and siRNA into compact nanoparticles.^{[ 113 ]} Compared with standard PEI, the CPC polymers exhibited enhanced transfection and gene silencing efficiency in the HEK293, L929, and COS7 cell lines, indicating low cytotoxicity. Furthermore, the β‐CD moieties on the CPC copolymers allowed for the supramolecular PEGylation of the polyplexes, improving their stability under physiological conditions. Interestingly, PEGylation led to increased gene silencing efficiency for the siRNA complexes, suggesting that PEG‐modified CPC systems offer a versatile platform for both pDNA and siRNA delivery. For targeted gene therapy, a PEGylated redox‐sensitive vector designed for FGFR‐mediated delivery was developed.^{[ 116 ]} This system consists of a β‐CD‐cross‐linked PEI host (MC11–PEI–β‐CD) complexed with adamantyl–SS–PEG, where the disulfide linkage enables intracellular PEG cleavage. In vitro and in vivo testing revealed that the complex effectively condenses pDNA into nanoparticles, enhances endosomal escape, and provides specific targeting to FGFR‐expressing carcinoma cells. This redox‐sensitive, FGFR‐targeting vector exemplifies the precision and adaptability that supramolecular pseudo‐BCPs bring to targeted gene delivery.

Finally, a multifunctional gene delivery system combines PCD with a redox‐sensitive, rhodamine‐tagged azobenzene branched polymer (Az–ss–BPDM–RhB) and Ad–PEG–FA for fluorescence traceability and targeting (Figure 9d).^{[ 134 ]} This PCD/Az–ss–BPDM–RhB/DNA polyplex demonstrated enhanced cell uptake and transfection efficiency after extended incubation, as well as good targeting ability and low cytotoxicity. The fluorescence‐traceable feature of this system allows visualization of the cellular distribution, and in vivo studies confirm its potential for safe, effective, and targeted gene delivery applications.

These examples highlight how pseudo‐BCP‐based gene carriers, enabled by host–guest chemistry, provide a versatile, modular approach to overcoming barriers in gene delivery and develop highly effective systems.

5.3. Other Biomedical Applications

In this section, we briefly explore the diverse capabilities of host–guest supramolecular systems beyond conventional drug and gene delivery, focusing on their adaptability as multifunctional platforms for combined therapies, imaging, and targeted diagnosis.

One promising application involves a codelivery system that integrates gene and drug therapy to improve cancer treatment efficacy. This system employs β‐CD–PEI600 as the host polymer and BM‐modified hyperbranched polyglycerol on a PCL‐initiated backbone (PCL–HPG–BM) as the guest polymer.^{[ 97 ]} The resulting PCL–HPG–PEI600 carrier uses pH‐sensitive inclusion complexation to facilitate the codelivery of DOX and the MMP‐9 shRNA plasmid (pMMP‐9) to breast cancer cells. The enhanced cellular uptake, superior in vivo transfection efficiency, and resulting significant inhibition of tumor proliferation and migration illustrate the effectiveness of this system. Compared with single‐agent therapies with either DOX or pMMP‐9, this codelivery platform has a more substantial therapeutic impact. Owing to its high serum stability and low toxicity, PCL–HPG–PEI600 offers a safe, efficient solution for combined cancer therapies, exhibiting the strong potential of host–guest systems in complex therapeutic delivery. In a related approach, Tang et al. reported a modular supramolecular micellar system for the codelivery of DOX and siRNA targeting PD‐L1, a key immune checkpoint protein that enables tumor immune evasion.^{[ 138 ]} The system was constructed using host–guest interactions between β‐CD and adamantane‐functionalized polymer segments, enabling the assembly of multifunctional micelles incorporating oligoethylenimine, PCL, and PEG in tunable ratios. These micelles exhibited excellent drug and gene loading capacity, serum stability, and codelivery efficiency. The platform achieved potent anticancer activity by combining DOX‐induced cytotoxicity with PD‐L1 gene silencing, demonstrating the utility of β‐CD‐based supramolecular architectures in immune‐assisted combination cancer therapy. Another study demonstrated a multifunctional nanoparticle platform that combines targeted imaging and light‐controlled gene delivery.^{[ 136 ]} This system employs PEI–β‐CD as the host polymer, which is assembled with two specific guest components: azobenzene–PEG–galactose (Az–PEG–Gal) and adamantane‐conjugated fluorescein (AD–FITC) (Figure 10a). The Az–PEG–Gal component enables targeted delivery to hepatocytes via the asialoglycoprotein receptor, while AD–FITC serves as an imaging agent. Through host–guest interactions, these nanoparticles efficiently condense DNA via electrostatic forces, forming stable core–shell structures. The azobenzene component allows light‐triggered detachment of the PEG chains, enabling controlled DNA release upon UV exposure. In vitro testing demonstrated effective cellular uptake, targeted HCC delivery, and enhanced transfection under light activation. This versatile platform exemplifies how host–guest assemblies can create sophisticated, multifunctional systems for combined gene delivery and bioimaging.

Figure 10.

Other interesting applications of CD‐based pseudo‐BCPs. a) A multifunctional nanoparticle platform utilizing PEI–β‐CD as the host polymer integrates targeted delivery via azobenzene–PEG–galactose (Az–PEG–Gal), imaging through adamantane‐conjugated fluorescein (AD–FITC), and light‐triggered DNA release. Reproduced with permission.^{[ 136 ]} Copyright 2014, The Royal Society of Chemistry. b) Extremely small iron oxide nanoparticles (ESIONPs) functionalized with adamantane‐modified PEG and β‐CD‐attached pH‐sensitive polysulfadimethoxine (PSDM) exhibit a tumor microenvironment‐triggered T₁ to T₂ contrast transition driven by pH‐induced nanoparticle aggregation. Reproduced with permission.^{[ 137 ]} Copyright 2022, American Chemical Society. c) PEGylated magnetic hybrid vesicles (SPMHVs), formed by self‐assembling polyrotaxane–PAA (PR–PAA) with magnetite nanoparticles and cross‐linking with 3‐mercaptopropyltrimethoxysilane (MPTMS), exhibit tunable morphologies and high T₂‐weighted MR contrast with a transverse relaxivity of 641.7 mm⁻¹ s⁻¹. Reproduced with permission.^{[ 112 ]} Copyright 2018, Elsevier B.V. d) A star‐shaped supramolecular copolymer, combining PCL–β‐CD (4sPCL–CD) as the host and adamantylamine‐modified poly‐l‐lactic‐block‐poly(N‐isopropylacrylamide‐co‐2‐hydroxyethylmethacrylate‐diethylenetriamine penta acetic acid) (AD–PLLA‐b‐P(NIPAM‐co‐HEMA‐DTPA)) as the guest, functions as a T₁‐weighted MRI contrast agent upon Gd³⁺ chelation and enables burst and thermally responsive drug release. Reproduced with permission.^{[ 100 ]} Copyright 2020, Elsevier B.V.

In addition to therapeutic applications, host–guest systems are revolutionizing imaging technologies, particularly in MRI. For example, PEGylated magnetic hybrid vesicles were constructed as T₂‐weighted MRI contrast agents (Figure 10c).^{[ 112 ]} These were formed by self‐assembling PR–PAA with magnetite nanoparticles, followed by cross‐linking with 3‐mercaptopropyltrimethoxysilane (MPTMS) and PEG modification. The vesicles exhibit high transverse relaxivity (641.7 mm⁻¹ s⁻¹) and tunable morphology, transitioning between vesicles and micelles by adjusting the concentration of Fe₃O₄. A specific formulation, SPMHVs‐30, demonstrated excellent contrast performance and passive tumor targeting through the EPR effect, highlighting its potential as a highly effective MRI contrast agent for detailed tumor imaging. To further expand the scope of MRI contrast agents, a star‐shaped supramolecular copolymer for diagnosis and controlled drug release has been developed that combines 4sPCL–β‐CD as the host and an adamantylamine‐modified poly‐l‐lactic‐block‐poly(N‐isopropylacrylamide‐co‐2‐hydroxyethylmethacrylate‐diethylenetriamine penta acetic acid) (AD–PLLA‐b‐P(NIPAM‐co‐HEMA‐DTPA)) as the guest (Figure 10d).^{[ 100 ]} Upon chelation with Gd³⁺ ions, the micelles act as T₁‐weighted MRI contrast agents, maintaining size stability for imaging while being biodegradable. This copolymer also offers a dual‐release mechanism, exhibiting burst and thermal‐responsive drug release behaviors, which enables precise control over drug administration, making it suitable for combined diagnosis and therapy applications. Finally, the design of pH‐responsive MRI contrast agents further demonstrates the versatility of host–guest chemistry. In this approach, extremely small iron oxide nanoparticles (ESIONPs) are functionalized with adamantane‐modified PEG and a pH‐sensitive polymer, polysulfadimethoxine (PSDM), attached to β‐CD (Figure 10b).^{[ 137 ]} This pH‐responsive ESIONP–PEG–PSDM system exhibits a unique T₁‐to‐T₂ contrast signal transition in acidic tumor environments, triggered by a hydrophilic‐to‐hydrophobic transition that promotes nanoparticle aggregation. This dynamic signal conversion allows enhanced tumor imaging precision and strongly suggests the potential of pH‐responsive MRI agents for accurate tumor diagnosis.

In summary, these applications reflect the multifaceted capabilities of host–guest supramolecular systems beyond their conventional roles in drug and gene delivery. By enabling fine‐tuned control over self‐assembly, responsiveness, and release mechanisms, host–guest systems are advancing therapeutic and diagnostic applications, contributing to the development of integrated platforms for targeted imaging, combined therapies, and responsive drug release.

6. Comparison of Cyclodextrin‐Based Pseudocopolymers and Covalent Copolymers: Functional Insights and Challenges

CD‐based pseudocopolymers offer a supramolecular alternative to traditional covalent copolymers, distinguished by their reversible host–guest interactions and modular assembly. While both classes of materials have been explored for biomedical applications, their underlying chemistries impart distinct advantages and constraints. This section provides a comparative overview of their differences and is essential for guiding rational material selection and future design strategies.

6.1. Modularity and Tunability

Supramolecular pseudocopolymers offer a level of modularity that is difficult to achieve with covalently linked copolymers. Polymer segments or functional domains can be incorporated by simply mixing components bearing complementary CD and guest moieties, thereby eliminating the need for de novo synthesis of new block copolymers.^{[ 139 ]} For instance, a polycation can be functionalized with CD, while a PEG chain can be modified with adamantane, allowing the formation of a pseudo‐PEG block upon mixing. This strategy enables postsynthetic tuning of properties such as hydrophilic fraction, targeting ligand density, and arm length through variation of component ratios. Zhang et al. demonstrated this principle by modulating host‐to‐guest ratios and using hosts with different arm lengths to adjust the transfection efficiency of a PEGylated gene delivery system.^{[ 107 ]} By contrast, covalent block copolymers possess a fixed composition upon synthesis, and any structural reoptimization necessitates a new synthetic route. Furthermore, the modular nature of pseudocopolymers facilitates rapid prototyping of functional assemblies. For example, various targeting ligands or stimuli‐responsive elements can be readily screened by exchanging the guest molecule, bypassing the need for labor‐intensive conjugation chemistry.

6.2. Architectural Complexity

Pseudocopolymers enable the construction of complex macromolecular architectures that would be synthetically demanding or impractical using covalent chemistry alone. For instance, miktoarm star polymers comprising five different polymer arms can be assembled via a combination of orthogonal host–guest interactions and metal coordination, whereas this endeavor would pose considerable synthetic challenges if approached through covalent linkage of all components in defined ratios. Similarly, hierarchical structures, including multilayered or multicomponent assemblies, can be constructed in a modular, stepwise fashion. For example, a CD‐bearing polymer may first associate with a hydrophobic polymer to form a supramolecular block, which can subsequently bind additional entities such as proteins or nanoparticles via secondary host–guest interactions. This level of hierarchical organization would typically require multiple synthetic steps and protection–deprotection strategies in a covalent framework.^{[ 140 ]} Nonetheless, supramolecular assembly introduces challenges in achieving precise stoichiometry, often resulting in a distribution of assembled species (e.g., star polymers with varying numbers of guest components). By contrast, covalent synthesis offers the potential for well‐defined, monodisperse structures. However, many CD‐based host–guest systems exhibit well‐characterized binding stoichiometries, often 1:1 per binding site, and methods such as controlled stoichiometric mixing and sequential assembly can be employed to enhance compositional uniformity in pseudocopolymer systems.

6.3. Dynamic Behavior and Reversibility

A hallmark of pseudocopolymers is their dynamic and reversible noncovalent bonding, in contrast to the permanently “locked” nature of covalent polymers. In CD‐based assemblies, these supramolecular interactions can dissociate and reform in response to environmental conditions, conferring beneficial properties such as stimuli‐responsiveness and controlled biodegradability. For example, a pseudo‐BCP can be designed to disassemble under acidic pH through guest expulsion, a functionality that is difficult to achieve in covalent systems without incorporating labile chemical linkages. Moreover, following completion of the intended therapeutic function, the assembly may degrade into smaller, renally excretable fragments such as CD‐bearing units, thereby reducing long‐term bioaccumulation and systemic burden.

However, the reversible nature of these bonds presents challenges in ensuring sufficient stability under physiological conditions, particularly in dilute environments or in the presence of competing guest molecules. By contrast, covalent BCPs retain structural integrity under such circumstances. To address this limitation, researchers commonly employ host–guest pairs with high binding affinity as well as multivalent interaction strategies to enhance kinetic stability. For instance, comb‐like or star‐shaped architectures containing multiple binding sites per particle can maintain robust structural integrity while preserving the capacity for triggered disassembly. In sum, supramolecular pseudocopolymers offer a favorable balance between dynamic responsiveness and functional stability, which can be highly advantageous in biomedical applications provided that the assemblies remain intact throughout their intended duration of action.

6.4. Biocompatibility and Clinical Considerations

CD‐based pseudocopolymers are supramolecular assemblies held together by noncovalent host–guest interactions, which make them intrinsically reversible and prone to disassemble under physiological conditions. This dynamic, degradable nature helps overcome the persistent, hard‐to‐degrade issues of conventional covalent polymers, lowering the risk of long‐term accumulation and polymer‐related toxicity while enhancing biocompatibility. In practice, when CD‐based pseudocopolymer networks dissociate, the fragments (e.g., individual CDs or small guest molecules) can be readily excreted (often via renal clearance), which effectively minimizes systemic toxicity and improves safety.^{[ 141 ]} Moreover, the building blocks themselves tend to be benign. CDs are biocompatible, biodegradable cyclic oligosaccharides that are widely used as pharmaceutical excipients and are even classified as “generally recognized as safe” by regulatory authorities.^{[ 142} , ^{143 ]} By contrast, covalent copolymers are held together by stable chemical bonds and must rely on hydrolysis or enzymatic cleavage to break down, leading to slower, less easily reversible degradation. This means covalent systems must be carefully designed so that any breakdown products are nontoxic, and they often undergo stringent evaluation to ensure no harmful accumulation. In short, the noncovalent nature of CD‐based pseudocopolymers lends them easier clearance, inherent biodegradability, and a favorable safety profile, whereas covalent copolymers offer structural robustness but demand thorough assessment of their degradation and biocompatibility in clinical development.

In essence, supramolecular pseudocopolymers present compelling advantages over traditional covalent copolymers in terms of modularity, adaptive assembly, and multifunctionality. These systems enable the rapid prototyping of sophisticated nanostructures and facilitate the incorporation of biologically responsive release mechanisms. Although they require careful consideration of stability under physiological conditions, this limitation can be addressed through the use of high‐affinity host–guest interactions and multivalent architectures. When appropriately designed, pseudocopolymer systems can exhibit comparable in vivo robustness to their covalent counterparts, while offering the additional benefits of controlled disassembly and structural tunability that are otherwise difficult to achieve with permanent covalent linkages.

7. Conclusions and Outlook

In conclusion, pseudo‐BCPs have demonstrated significant potential in advancing drug and gene delivery systems by enabling precise targeting, controlled release, and responsiveness to environmental stimuli. By employing tailored host–guest chemistry, these supramolecular systems offer structural versatility and functional adaptability. Through the incorporation of stimuli‐responsive features such as pH sensitivity, temperature responsiveness, and redox‐triggered release, pseudo‐BCPs improve therapeutic efficacy while minimizing off‐target effects. These characteristics directly address key challenges in drug delivery, including improving drug solubility, increasing drug stability in biological environments, and ensuring site‐specific action. As a result, pseudo‐BCPs represent a powerful toolkit for developing sophisticated, patient‐tailored therapeutic delivery solutions.

Despite their promise, the intricate design and synthesis required for pseudo‐BCP systems present notable challenges. The development and characterization of these complex architectures are often resource‐intensive, involving multiple synthesis steps and specialized equipment, which may limit their scalability and potential for widespread clinical application. Furthermore, while many preclinical studies have shown encouraging outcomes, long‐term studies on the biocompatibility, biodistribution, and pharmacokinetics of these materials are essential for reliably predicting there in vivo behavior and safety. These studies are crucial, as they will help identify any unforeseen side effects or accumulation issues, which are critical for establishing the safety profile necessary for regulatory approval and eventual clinical use.

Future research should focus on refining synthetic methodologies and creating modular designs that allow properties to be tuned more efficiently for specific therapeutic applications. Such efforts could streamline the process of adapting these materials to diverse medical needs, making them more accessible for various treatment strategies. Additionally, improving our understanding of the biodegradability, immunogenicity, and long‐term pharmacological behavior of pseudo‐BCP systems will be essential for their safe and predictable transition from laboratory models to clinical applications. With continued progress in addressing these challenges, pseudo‐BCPs hold substantial promise as the next generation of targeted drug and gene delivery systems, potentially transforming treatment paradigms across a broad spectrum of medical applications, including cancer, genetic disorders, and infectious diseases. Looking ahead, the convergence of pseudo‐BCP technology with fields such as systems biology, artificial‐intelligence‐guided material discovery, and bioresponsive electronics may unlock entirely new modalities of therapeutic delivery. This emerging interdisciplinarity has the potential not only to refine current approaches but to fundamentally reshape how we design, deploy, and personalize drug and gene delivery systems.

Beyond biomedical formulations, future directions for CD‐based pseudocopolymers lie in pushing the frontiers of supramolecular design. One promising approach is to develop orthogonal host–guest systems in which multiple, noninterfering recognition motifs are integrated into one polymer architecture. For example, CD complexes can be combined with a second macrocycle–guest pair (such as a calixarene‐based inclusion complex) to create multicomponent assemblies. A proof of concept is the construction of a linear ternary polymer using distinguishable CD and calixarene host–guest interactions.^{[ 144 ]} Such orthogonal recognition elements enable self‐sorted assembly of copolymers, opening avenues for programmed sequences or hierarchically structured networks. Achieving greater precision in supramolecular polymer architecture is another compelling challenge. Concepts like integrative self‐sorting and sequence‐controlled supramolecular polymerization are being explored to impart the sort of structural order seen in biological assemblies.^{[ 145 ]} For example, by programming complementary CD–guest pairs or kinetic pathway control, researchers aim to attain sequence‐defined supramolecular copolymers, wherein the placement of CD‐bearing and guest‐bearing units follows a predetermined order, analogous to the precise sequences in proteins or nucleic acids.

In parallel, bioinspired and synthetic biology approaches are emerging as exciting avenues. For instance, modifying natural biopolymers (e.g., hyaluronic acid or peptides) with CD or guest moieties enables the precision positioning of host–guest units along a biological backbone, yielding hybrid supramolecular networks that combine the biocompatibility of natural polymers with the switchable functionality of CD complexes. There is also interest in engineering protein‐based hosts or orthogonal binding partners informed by structural biology, which could interface with CD motifs or even create in vivo assembly routes. Such forward‐looking strategies from orthogonal recognition motifs and stimuli‐responsive, self‐regulating systems to biointegrated supramolecular constructs demonstrate a broad vision for CD‐based pseudocopolymers. By embracing these concepts, future researchers can transcend the current focus on drug delivery to develop adaptive, precision‐engineered supramolecular polymers informed by the principles of molecular recognition and the ingenuity of modern chemical biology.

While this review aims to provide a comprehensive overview of the current landscape and potential future directions for pseudo‐BCP applications, it is limited in scope and may not cover all recent advancements or emerging methods. New developments in synthetic strategies, characterization techniques, and biological applications are constantly evolving and may offer further insights beyond the scope of this review. Nonetheless, this paper presents pseudo‐BCPs as promising tools for enabling safer, more effective, and more personalized therapeutic strategies. As research continues to advance, the insights provided here may facilitate future innovations in this promising field.

Conflict of Interest

The authors declare no conflict of interest.

Biographies

Wilson Wee Mia Soh received his Ph.D. from the Department of Biomedical Engineering at the National University of Singapore (NUS) in 2023. He is currently a Postdoctoral Research Fellow at the NUS Institute for Functional Intelligent Materials, where he explores the life science applications of conjugated oligoelectrolytes. His research interests span polymer design and synthesis, nanomedicine, supramolecular biomaterials, and advanced bioimaging techniques, with a focus on developing innovative solutions for biomedical applications.

Jun Li received his Ph.D. from the University of Osaka in Japan. He is currently a Professor in the Department of Biomedical Engineering, National University of Singapore (NUS). Additionally, Prof. Li serves as a principal investigator at NUS Environmental Research Institute and NUS Research Institutes in Suzhou and Chongqing. His research focuses on the development of innovative supramolecular smart materials and hydrogels derived from both synthetic and bio‐based polymers for applications in nanomedicine, tissue engineering, and environmental sustainability. He has published 230 papers, with an h‐index of 73 and a total of 17,600 citations according to the Web of Science.

Soh W. W. M. and Li J., “Cyclodextrin‐Based Pseudocopolymers and Their Biomedical Applications for Drug and Gene Delivery.” Small 21, no. 36 (2025): 21, e01304. 10.1002/smll.202501304