ABSTRACT Hyaluronic acid (HA), a naturally occurring glycosaminoglycan, has emerged as a versatile biomaterial for biomedical applications owing to its biocompatibility, biodegradability, and intrinsic affinity for CD44 and related receptors. Recent advances in supramolecular chemistry have enabled the construction of macrocyclic HA assemblies incorporating cyclodextrins, cucurbiturils, calixarenes, and pillararenes, creating dynamic, injectable, and stimuli‐responsive platforms for therapeutic delivery and tissue regeneration. This review provides a macromolecule‐centric, translationally oriented synthesis of HA macrocycle systems, critically comparing construction strategies (HA molecular weight, grafting chemistry, solvent conditions), drug inclusion capacity across hydrophobic, hydrophilic, and biological payloads, and rheological design rules governing injectability, bioprinting fidelity, and tissue‐specific performance. We integrate structure assembly function relationships with emerging clinical use‐cases in oncology, ocular therapy, wound healing, cartilage/bone repair, and gene delivery. Importantly, we identify key translational bottlenecks scalability, batch reproducibility, long‐term safety of macrocycles, and regulatory classification and propose design principles and manufacturing considerations to bridge laboratory innovation with clinical deployment. Looking forward, multi‐host architectures, hybrid crosslinking strategies, and integration with 3D bioprinting and immunoengineering are highlighted as enabling directions for next‐generation HA supramolecular therapeutics. This review aims to guide rational design of clinically viable HA macrocyclic assemblies for precision biomaterials and regenerative medicine.
Sathishkumar et al. (Wed,) studied this question.
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