A Quercetin Nanocarrier‐Loaded Dual Network Injectable Hydrogel for Mesenchymal Stem Cells (MSCs) Delivery Targeting Osteoarthritis

ABSTRACT Osteoarthritis (OA) is a progressive, chronic disorder of the musculoskeletal system affecting more than 500 million individuals globally. Current treatment strategies primarily provide palliative care, with limited potential to alter disease progression or reverse tissue deterioration. Stem cell transplantation holds promising results. But poor cell retention and survival due to ROS and inflammation in OA lead to subpar therapeutic outcomes. In this study, we developed a dual‐network gelatin methacrylate (GelMA) and κ‐carrageenan‐based injectable hydrogel loaded with antioxidant quercetin‐PLGA nanoparticles for stem cell delivery to treat OA. Physicochemical studies demonstrated stable gelation, controlled degradation, and self‐healing properties. In vitro studies revealed that the sustained release of quercetin effectively scavenged intracellular ROS, reduced the expression of pro‐inflammatory factors such as IL6, COX2, NFκβ, and TNFα, and increased the expression of TGFβ, IL4, SOX9, COL2, and ACAN, which are responsible for inflammation control and cartilage tissue regeneration. The sustained release of nanoparticles also enhanced the M1‐to‐M2 macrophage transition and collagen II deposition. In vivo studies demonstrated that the nanoparticle‐loaded stem cell‐encapsulated hydrogel increased glycosaminoglycan deposition, reduced inflammation, and improved joint mobility and cartilage repair. Thus, this antioxidant hydrogel‐based cell delivery system demonstrated suitability for OA therapy.