Dihydroxyacetone nanoparticles ameliorate osteoarthritis via P21-mediated regulation of chondrocyte repair

Osteoarthritis (OA) is a disease characterized by progressive cartilage degeneration. P21, as a cell cycle regulator, participates in maintaining cartilage homeostasis. This study aimed to evaluate the therapeutic potential of dihydroxyacetone (DHA) and its hyaluronic acid methacrylate (HAMA)-DHA nanoparticles in improving OA through the P21-mediated PI3K/Akt signaling pathway. Findings from the analyzed human cohorts and animal models revealed significantly reduced P21 expression in OA cartilage, which negatively correlated with disease severity within the examined stages. P21 overexpression enhanced chondrocyte anabolism, alleviated oxidative stress, and suppressed catabolic responses, whereas P21 deficiency exacerbated cartilage degeneration. The combined analysis of RNA Sequencing and metabolomics indicated that DHA is a key metabolic node regulating P21. DHA treatment restored P21 levels, alleviated oxidative stress via the P21-mediated PI3K/Akt signaling pathway, promoted expression of anabolic markers (SOX9, COL2, and ACAN), and suppressed catabolic markers (MMP13, ADAMTS-4, and COL10). Compared to free DHA, DHA@HAMA nanoparticles significantly enhanced stability, cellular compatibility, and chondroprotective effects while enabling sustained release. This approach was observed to further promote P21-mediated PI3K/Akt signaling, which corresponded with mitigated cartilage erosion, subchondral bone loss, and OA severity. This study establishes that DHA exerts critical protective effects in OA via the P21-mediated PI3K/Akt signaling pathway. DHA@HAMA nanoparticles alleviate OA progression by more effectively enhancing P21 expression and function, offering a promising new therapeutic strategy for OA treatment.