MMP13-responsive hydrogel microspheres for osteoarthritis treatment by precise delivery of celecoxib

Abstract

Osteoarthritis (OA) is characterized by cartilage degradation, inflammatory responses, and osteophyte formation. Matrix metalloproteinase 13 (MMP13) is a hallmark of OA development, and increased MMP13 expression is closely associated with extracellular matrix degradation. MMP13 expression varies significantly at different stages of OA progression. While cyclooxygenase 2 (COX-2) inhibitors are commonly used to treat OA, their long-term systemic administration increases the risks of adverse effects. Therefore, with the aim of achieving localized and responsive delivery of the COX-2 inhibitor celecoxib, the current study investigated an innovative MMP13-responsive micro-nano hydrogel microsphere system. Celecoxib-loaded cationic liposomes are non-covalently attached within the microsphere, enabling controlled drug release for OA treatment. In an OA environment with elevated MMP13 expression, the system is degraded via the action of MMP13 substrate peptide (MMP13sp), facilitating accelerated release of drug-loaded liposomes to improve the inflammatory microenvironment and treat OA rapidly. Compared to a phosphate-buffered saline solution with hyaluronidase (HAase), the prepared hyaluronic acid methacrylate microspheres HAMA/MMP13sp/Lipo@celecoxib exhibited rapid degradation in a solution containing a physiological concentration of MMP13/HAase, demonstrating specific enzyme responsiveness for precise anti-inflammatory drug release. The MMP13-responsive hydrogel microsphere system achieves intelligent and controllable drug release in OA, effectively decelerating disease progression and promoting articular cartilage repair.