Nano-Armor Empowers Mesenchymal Stem Cells to Actively Target and Reverse Synovial Inflammation in Rheumatoid Arthritis.

Abstract

Mesenchymal stem cell (MSC) therapy for rheumatoid arthritis (RA) remains hindered by the oxidative-induced pro-inflammatory synovial microenvironment, which largely impairs MSC homing, survival, and immunomodulatory function. Although nanomaterial modification holds promise for enhancing MSC therapeutic efficacy, conventional intracellular modification approaches carry risks of cytotoxicity and unpredictable stem cell fate alteration. Here, we empower MSCs with a surface-anchored, multifunctional RGD-MXene/MnO₂ nano-armor (RMM). MXene, with its large specific surface area, supports the in-situ growth of MnO₂ nanozymes and conjugation of RGD targeting peptides, while enabling stable covalent anchoring onto the MSC membrane via click chemistry. The RMM-armored MSCs exhibit robust protection against ROS-induced damage and fully restored immunomodulatory capacity due to the cascade catalase- and superoxide dismutase-like activities of MnO2, efficiently promoting macrophage polarization from pro-inflammatory M1 type to anti-inflammatory M2 type. In RA mouse models, the RGD peptide facilitates active MSC homing to inflamed synovial tissues by specifically recognizing integrin αvβ3. Thus, RMM@MSCs not only alleviate synovial inflammation but also prevent bone destruction and cartilage erosion, achieving highly efficient RA therapy with only one dose. This surface modification strategy resolves the long-standing translational barriers of conventional MSC therapy, providing a versatile and translatable platform for treating RA and other inflammatory diseases. STATEMENT OF SIGNIFICANCE: Although mesenchymal stem cells (MSCs) are promising for rheumatoid arthritis (RA) due to their inherent immunomodulatory properties, their translation is hindered by poor homing to inflammatory joints and ROS-induced functional impairment. This work reports the use of a multifunctional RGD-MXene/MnO2 (RMM) nano-armor to enhance MSC therapy in RA. Specifically, MXene provides a large specific surface area for the in-situ growth of MnO2 nanoenzyme and the peptide conjugation, as well as the covalent anchoring on MSCs (favoring safe surface modification); MnO2's cascade enzyme-like activity establishes an antioxidant shield to reverse ROS-induced MSC apoptosis and exhaustion (maintaining MSC viability and biofunctions); RGD peptide targets highly expressed integrin αvβ3 in synovial pannus (enabling active MSC homing). Thus, the nano-armor-modified RMM@MSCs significantly inhibits synovitis, alleviates symptoms, and mitigates joint destruction.