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.