Retinoic Acid-Loaded Cartilage Organoids Attenuate Chondrocyte Senescence in Osteoarthritis.

Background: Osteoarthritis (OA) is a debilitating degenerative joint disease characterized by chondrocyte senescence and cartilage degradation. Despite extensive research, effective therapeutic strategies targeting the underlying mechanisms of chondrocyte senescence remain limited. Methods: We employed an integrated multi-omics approach combining weighted gene co-expression network analysis (WGCNA) and machine learning algorithms with the SenMayo gene set to identify key senescence-associated genes in OA. Single-cell RNA sequencing was used to characterize distinct chondrocyte subpopulations. Computational screening, molecular docking, and dynamics simulations identified potential therapeutic compounds. We engineered a triphasic gelatin methacryloyl/hyaluronic acid methacryloyl (GelMA/HAMA) cartilage organoid system for controlled delivery of retinoic acid (RA) and evaluated its efficacy in vitro and in a rat destabilization of the medial meniscus (DMM) model of OA. Results: Our bioinformatic analysis identified Conclusion: Our findings establish RA delivered via biomimetic cartilage organoids as a promising therapeutic strategy that addresses the cellular mechanisms underlying OA progression. This approach may represent a paradigm shift from symptom management to disease modification by targeting chondrocyte senescence and promoting cartilage regeneration, offering new avenues for developing effective treatments for OA.