MXene-Mediated Nanocarrier Delivery Enhances the Chondroprotective Effects of Quercetin in Experimental Osteoarthritis

Osteoarthritis (OA) is a common chronic joint disease that severely affects patients' quality of life. Quercetin, a natural flavonoid, exhibits chondroprotective effects, though its bioavailability through regular oral consumption is limited. In this study, we employed two-dimensional MXene nanosheets as a nanocarrier to facilitate targeted intracellular delivery of quercetin, aiming to enhance its therapeutic efficacy against OA. Methods: Porous Ti₃C₂Tₓ MXene nanosheets were synthesized via selective etching and then loaded with quercetin through physical adsorption. Material characterization was performed using transmission electron microscopy (TEM), scanning electron microscopy (SEM), ultraviolet-visible spectroscopy (UV-Vis), dynamic light scattering (DLS), and in vitro release assays. For in vitro evaluation, IL-1β-stimulated primary mouse articular chondrocytes (ACs) were treated with free quercetin or MXene-loaded quercetin, followed by assessments of cell viability, apoptosis, cell cycle progression, migration, oxidative stress markers, and ferroptosis-related protein expression. For in vivo validation, a destabilization of the medial meniscus (DMM) mouse model of OA was established to assess cartilage morphology, ferroptosis markers, and histological changes after intra-articular injection of treatments. MXene-loading significantly enhanced quercetin's protective effects in IL-1β-induced primary mouse ACs, including improved cell viability and proliferation, reduced apoptosis, alleviated oxidative stress, and suppression of ferroptosis. In OA mice, MXene-quercetin treatment more effectively preserved cartilage integrity and inhibited ferroptosis compared with free quercetin. These findings suggest that MXene can serve as a biocompatible carrier to improve quercetin delivery in osteoarthritis models, supporting its potential for further preclinical evaluation.