A Honeysuckle-Decorated Nanoimmunomodulator Hijacks Macrophage-BMSC Crosstalk to Promote Arthritic Regeneration

Osteoarthritis (OA) is a chronic inflammatory joint disorder characterized by persistent synovitis and progressive cartilage degradation, driven primarily by dysregulated macrophage polarization and impaired chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). In this study, we innovatively developed a honeysuckle flavonoid-modified ruthenium nanocluster (RuNC@HS) nanozyme that exhibits dual superoxide dismutase (SOD) and catalase (CAT)-mimicking activities, enabling efficient reactive oxygen species (ROS) scavenging and immunomodulation. In vitro and in vivo experiments demonstrated that RuNC@HS inhibits NLRP3/caspase-1-mediated pyroptosis in BMSCs and blocks the subsequent HMGB1-induced activation of the TLR4/STAT3 pathway in macrophages, thereby disrupting a maladaptive pro-inflammatory feedback loop. These mechanisms significantly enhanced BMSC migration, chondrogenic differentiation, and M2 macrophage polarization. In a murine OA model induced by anterior cruciate ligament transection (ACLT), intra-articular administration of RuNC@HS markedly reduced osteophyte formation, restored subchondral bone architecture, improved gait function, and promoted cartilage matrix synthesis, while downregulating catabolic enzyme expression. Metabolomic profiling further revealed that RuNC@HS uniquely modulates anti-inflammatory lipid metabolism pathways, particularly α-linolenic acid metabolism. For the first time, this study highlights the dual innovative aspects of integrating traditional herbal medicine with precise nanozyme design and deeply deciphering BMSC-macrophage crosstalk as an immunometabolic regulatory strategy, offering a novel and synergistic therapeutic approach for OA. Scheme. Schematic illustration of (a) the structural units of RuNC@HS, along with (b) the therapeutic mechanism in Osteoarthritis Therapy.