Accelerated cartilage regeneration via chondrocyte metabolic reprogramming using nano-steroid-conjugated mesenchymal stem cells in osteoarthritis

<b>Background:</b> 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 <i>in vivo</i> efficacy and an incomplete understanding of the underlying pathological mechanisms and therapeutic targets. <b>Methods:</b> 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 <i>in vitro</i> using osteoarthritis patient-derived chondrocytes and peripheral blood mononuclear cells (PBMCs), and <i>in vivo</i> 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). <b>Results:</b> 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. <i>In vivo</i>, 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. <b>Conclusions:</b> 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.