Multi-omics-guided HAMA/PLMA bioink integrating mechanical support, antibacterial protection, and liposomal kartogenin for cartilage regeneration.

Articular cartilage regeneration requires a bioink that combines printability with mechanical support, antibacterial functionality, and pro-chondrogenic bioactivity. Here, a 3D-printable hyaluronic acid methacrylate/polylysine methacrylamide (HAMA/PLMA, HP) hybrid hydrogel incorporating kartogenin-loaded liposomes (KGN@Lipo) was developed for articular cartilage regeneration. Integrated transcriptomic and metabolomic profiling identified HP-associated signatures related to ECM interaction and mechanotransduction, and selected mechanosensitive genes were subsequently validated by qRT-PCR. A second multi-omics comparison showed that KGN@Lipo@HP was associated with attenuated inflammatory-catabolic signaling and a matrix-protective cellular state relative to the Control condition. Physicochemical characterization confirmed rapid photocuring, reliable print fidelity, improved compressive behavior, cyclic resilience, and a tunable porous architecture, while liposomal loading preserved the optimized mechanical baseline. Functionally, KGN@Lipo@HP maintained high cytocompatibility, showed lower intracellular ROS-associated fluorescence, markedly inhibited Staphylococcus aureus growth, and promoted in vitro chondrogenesis, as evidenced by intensified cartilage-matrix staining and increased COL2 and ACAN expression. In the rabbit defect model, KGN@Lipo@HP was associated with the most extensive cartilage-like matrix deposition and the lowest histological scores among the tested groups. Compared with Control, the treated defects also exhibited distinct immunohistochemical profiles for cartilage formation and tissue remodeling. Together, these findings support an HP-based bioink platform that integrates mechanical support, antibacterial protection, and liposomal KGN bioactivity to support a cartilage-permissive regenerative microenvironment.