Macrocyclic Supramolecular Assemblies Based on Hyaluronic Acid and Their Biological Applications

ConspectusHyaluronic acid (HA), which contains multiple carboxyl, hydroxyl, and acetylamino groups and is an agent that targets tumors, has drawn great attention in supramolecular diagnosis and treatment research. It can not only assemble directly with macrocyclic host–guest complexes through hydrogen bonding and electrostatic interactions but also can be modified with macrocyclic compounds or functional guest molecules by an amidation reaction and used for further assembly. Macrocycles play a main role in the construction of supramolecular drug carriers, targeted imaging agents, and hydrogels, such as cyclodextrins and cucurbit[n]urils, which can encapsulate photosensitizers, drugs, or other functional guest molecules via host–guest interactions. Therefore, the formed supramolecular assemblies can respond to various stimuli, such as enzymes, light, electricity, and magnetism for controlled drug delivery, enhance the luminescence intensity of the assembly, and improve drug loading capacity. In addition, the nanosupramolecular assembly formed with HA can also improve the biocompatibility of drugs, reduce drug toxicity and side effects, and enhance cell permeability; thus, the assembly has extensive application value in biomedical research. This Account mainly focuses on macrocyclic supramolecular assemblies based on HA, especially their biological applications and progress in the field, and these assemblies include (i) guest-modified HA, such as pyridinium-, adamantane-, peptide-, and other functional-group-modified HA, along with their cyclodextrin and cucurbit[n]uril assemblies; (ii) macrocycle-modified HA, such as HA modified with cyclodextrins and cucurbit[n]uril derivatives and their assembly with various guests; (iii) direct assembly between unmodified HA and cyclodextrin- or cucurbit[n]uril-based host–guest complexes. Particularly, we discussed the important role of macrocyclic host–guest complexes in HA-based supramolecular assembly, and the roles included improving the water solubility and efficacy of hydrophobic drugs, enhancing the luminescent intensity of assemblies, inducing room temperature phosphorescence and providing energy transfer systems, constructing multi-stimulus-responsive supramolecular assemblies, and in situ formation of hydrogels. Additionally, we believe that obtaining in-depth knowledge of these HA-based macrocyclic supramolecular assemblies and their biological applications encompasses many challenges regarding drug carriers, targeted imaging agents, wound healing, and biomedical soft materials and would certainly contribute to the rapid development of supramolecular diagnosis and treatment.