Abstract
Osteoarthritis (OA) is a prevalent joint disease characterizedby chronic, progressive inflammation and cartilage degeneration, for which current treatments remain limited. In this study, we propose a dual-drug delivery strategy that simultaneously suppresses inflammation and rejuvenates impaired cartilage by incorporating kartogenin (KGN) and methylprednisolone hemisuccinate (MPHS) into a single microsphere system with sequential release in the local microenvironment. To achieve coordinated dual-drug release, KGN and MPHS were loaded into the inner core and outer layer of the microspheres, respectively. Both KGN and MPHS exhibited sustained release profiles; however, MPHS showed a shorter burst-release phase than KGN due to the protective effect of the outer layer. The release of MPHS effectively suppressed interleukin-1β (IL-1β)-induced inflammation in bone marrow stromal cells (BMSCs) pellets, thereby enhancing KGN-mediated chondrogenic differentiation of BMSCs in vitro. In parallel, sustained delivery of KGN also led to the recruitment of BMSCs and subsequent chondrogenesis, ultimately leading to cartilage rejuvenation. Importantly, the sequential release of KGN and MPHS from the dual-drug microspheres synergistically enhanced in vitro chondrogenic differentiation of BMSCs, resulting in concomitant inflammation alleviation and cartilage repair. Collectively, these findings demonstrate that the KGN/MPHS-incorporated microspheres possess dual chondrogenic and anti-inflammatory functions and represent a promising therapeutic strategy for OA treatment.