Tailoring alkyl modification patterns in hyaluronic acid derivatives serving as carriers for enhanced kartogenin delivery and chondrogenic responses

Cartilage diseases often worsen with age and require orthopedic treatment. To reduce the need for surgery, developing new methods and biomaterials to stimulate and support cartilage regeneration is essential. Among the most promising options are drug delivery systems based on hyaluronic acid (HA), a natural component of the extracellular matrix, known for its biocompatibility, biodegradability, and adjustable chemical modification. In this study, we systematically tailored alkyl modification patterns in HA by introducing alkyl chains of varying lengths and degrees of substitution. Following comprehensive physicochemical characterization, the resulting amphiphilic derivatives formed polyelectrolyte aggregates suitable for controlled delivery of bioactive molecules. Kartogenin (KGN), a small, moderately hydrophobic molecule with chondroprotective effects, was used as a model drug to test the system's potential. The engineered HA derivatives efficiently encapsulated KGN, and specific formulations promoted chondrogenesis in both 2D and 3D cultures by upregulating key chondrogenic markers. These findings highlight the importance of precise alkyl pattern design in modulating HA-based carrier behavior and pave the way for further optimization, including refined substitution strategies, ligand conjugation approaches, and expanded biocompatibility studies toward future in vivo applications. • Alkylated hyaluronic acid (HA) derivatives were synthesized and characterized. • Tailoring the modifications enabled HA self-assembly and encapsulation of kartogenin. • Kartogenin (KGN) release profiles depend on the composition of alkylated HA. • Selected HA-KGN systems enhanced chondrogenic gene expression in 2D and 3D models.