Abstract
Background: Osteoarthritis (OA) is a prevalent and debilitating chronic disease for which there are currently no approved disease-modifying osteoarthritis drugs (DMOADs). While mesenchymal stem cells (MSCs) have emerged as promising DMOAD candidates, their clinical application is hindered by inconsistent in vivo efficacy and an incomplete understanding of the underlying pathological mechanisms and therapeutic targets. Methods: To address these limitations, we developed a novel therapeutic strategy by conjugating MSCs with steroid-loaded gold nanostars (MSC-Au-Steroid). The effects of MSC-Au-Steroid were assessed in vitro using osteoarthritis patient-derived chondrocytes and peripheral blood mononuclear cells (PBMCs), and in vivo using a monosodium iodoacetate (MIA)-induced mouse model of osteoarthritis. Key assessments included anti-inflammatory activity, metabolic profiling (glycolysis and oxidative phosphorylation), mitochondrial function, reactive oxygen species (ROS) production, mTOR signaling, and immunomodulatory effects on Th1, Th17, and regulatory T cells (Tregs). Results: MSC-Au-Steroid demonstrated strong anti-inflammatory effects in OA chondrocytes, promoted cartilage regeneration, and normalized altered metabolic profiles under inflammatory conditions. It improved mitochondrial function and suppressed excessive ROS production via mTOR signaling regulation. In vivo, MSC-Au-Steroid alleviated clinical symptoms and preserved cartilage integrity in the MIA-induced OA mouse model. Furthermore, it exhibited immunomodulatory effects in both mouse and patient-derived PBMCs, inhibiting Th1 and Th17 responses while promoting Treg induction and restoring immune tolerance. Conclusions: MSC-Au-Steroid represents a promising multifactorial therapeutic candidate for OA by targeting both metabolic reprogramming and immune modulation. These findings provide strong evidence that MSC-Au-Steroid acts as a disease-modifying agent, addressing multiple pathological factors and offering superior efficacy compared to current therapies.