Bridging Scales: Integrating Hyaluronan-Based Nanoencapsulation into 3D Hydrogel Constructs for Advanced Therapeutics-A Comprehensive Review.

The integration of nanoscale drug carriers within macroscale three-dimensional (3D) hydrogel architectures represents a paradigm shift in biomaterials design, enabling hierarchical control over therapeutic delivery. Hyaluronan (hyaluronic acid, HA), a native glycosaminoglycan of the extracellular matrix (ECM), has emerged as an exceptionally versatile building block for both nanoscale encapsulation systems and macroscale hydrogel scaffolds. This comprehensive review examines the rationale, fabrication strategies, and therapeutic applications of hyaluronan-based nanoencapsulation integrated within 3D hydrogel constructs, highlighting how this multiscale approach bridges the gap between molecular drug stabilization and tissue-level regenerative outcomes. We explore the chemical versatility of HA, the design principles of nanoencapsulation systems, the synthesis of 3D HA hydrogels, and the strategies for integrating these systems into unified therapeutic platforms. Applications in 3D bioprinting, injectable hydrogels, organ-on-a-chip models, cancer therapy, and tissue regeneration are critically evaluated. Finally, we discuss translational challenges, regulatory considerations, and future perspectives for clinical implementation of these advanced therapeutic systems.