1. Introduction
Beta-CD is a unique amphiphilic cyclic macromolecule characterized by the presence of multiple hydroxyl groups, making it broadly applicable across various scientific fields, particularly in biomedicine, chemistry, food science, and environmental science1[]. Beta-CD has a distinct bucket-shaped cavity with an inner diameter and depth of approximately 0.8 nm each. This macrocyclic feature provides a versatile foundation for the construction of beta-CD/drug inclusion complexes, which are primarily driven by van der Waals forces, hydrogen bonding, and hydrophobic interactions2[]. The capacity to encapsulate potential pharmaceutical molecules enhances their bioavailability, masks odors, improves water solubility, and reduces drug toxicity. Consequently, beta-CD can mitigate undesirable properties of pharmaceutical compounds due to these characteristics. As a result, this field is rapidly advancing in drug delivery and bioavailability by leveraging beta-CD’s host–guest interactions and selective modifications3[].
In recent years, with the rise of intelligent drug delivery systems and advancements in biomedical materials, the design and assembly of drug carriers have become increasingly complex, hindering clinical translation4[]. Dual and multi-stimuli-responsive beta-CD nanoparticles, developed through various chemical modifications, are continuously emerging. Despite significant progress, many intelligent beta-CD drug delivery techniques remain at the conceptual and laboratory stages, impeding practical applications. As beta-CD supramolecular structures become more intricate, the number of uncontrollable factors increases significantly. Furthermore, challenges in beta-CD-based drug delivery systems are mainly due to a lack of understanding of in vivo catabolism and behavior. However, researchers are actively addressing these issues to develop clinical and translational solutions for effectively treating various tumors. Simple and effective drug delivery systems are gaining attention for their optimal therapeutic effectiveness, achieved through rational and biomimetic design5[]. For controlled release drug carriers, the regulation of drug release behavior, including timing and dosage, should respond to external stimuli. Overall, drug carriers can modulate drug release based on stimulus intensity, which includes endogenous stimuli (e.g., pH, redox, and enzymes)6-10[] and exogenous stimuli (e.g., temperature, light, and ultrasound)11[].
The design of topologically intriguing beta-CD macromolecular architectures plays a critical role in enhancing drug release behavior, simplifying complex systems, and improving drug load capacity, colloidal stability, and hydrophilic and hydrophobic properties, primarily due to the versatility of beta-CD. Notably, the hydrophilic and hydrophobic properties are improved by several magnitudes. Classes of beta-CD topologies, including cage-like, chain-like, bridged structures, polyrotaxanes, and star/multi-arm polymer nanostructures, are unique not only from a topological geometry perspective but also in their relevance to programmed drug delivery12[]. These structures are promising candidates for forming inclusion complexes with guest molecules, enabling effective drug encapsulation. Various medicinal molecules, such as antitumor drugs, anti-diabetic drugs, anti-inflammatory agents, and antihypertensive drugs, have been encapsulated in beta-CD-based topology systems for long-term release13-17[]. Recent studies have shown that functionalizing beta-CD can significantly improve application outcomes. For example, Zhang et al. developed an acid-sensitive poly(beta-CD)-based multifunctional supramolecular gene vector, consisting of poly(beta-CD) as the backbone and acetal bond-linked PGEA as the arms through atom transfer radical polymerization (ATRP) and ring-opening reactions18[]. Chen et al. proposed a multicharge beta-CD supramolecular assembly based on an amphiphilic beta-CD bearing seven hexylimidazolium units, which demonstrated specific cancer cell targeting and controlled drug release abilities19[]. Colesnic et al. designed difunctionalized beta-CD to create a porous organic hierarchical supramolecular assembly through regioselective functionalization, resulting in a porous organic architecture20[]. The performance of beta-CD macromolecules is enhanced by strong intramolecular interactions within beta-CD fragments. Consequently, there is an urgent need for simple and efficient methods to develop beta-CD macromolecular architectures that extend the physicochemical performance and drug loading behavior of beta-CD2122[, ]. In particular, long-range interactions between beta-CD fragments are utilized to build cage-like, chain-like, and bridged structures.
Due to its large-ring structure and multiple hydroxyl groups, beta-CD is an excellent material for potential polymer crosslinking network structures. Consequently, we designed a nanocage-like drug carrier using beta-CD as the molecular building blocks and imine/disulfide bridges as switchable units in a straightforward manner. The network structure facilitates the distribution of hydrophobic pharmaceutical molecules within the nanocage-like space through host-guest and hydrophobic interactions, enhancing drug loading and delivery. Additionally, the proposed beta-CD nanocage exhibited a nano-sized structure with triggered doxorubicin (DOX) release in response to acidic and reductive environments. Overall, the assembly of the beta-CD supramolecular structure becomes significantly simpler, and uncontrollable factors are greatly reduced23[]. This drug delivery system adheres to the fundamental principle of treating the correct patient, at the right time, with the precise drug dose, potentially improving treatment outcomes for various diseases.