Nanoplastics exposure accelerates the progression of osteoarthritis via lysosomal destabilization-mediated pyroptosis

INTRODUCTION: Nanoplastics (NPs), as emerging environmental pollutants, are increasingly detected in human musculoskeletal tissues, but their impact on osteoarthritis (OA) pathogenesis remains unclear. OBJECTIVES: This study aimed to investigate whether NPs exposure accelerates osteoarthritis progression in osteoarthritic mice, to elucidate the underlying molecular mechanisms, and to evaluate the therapeutic potential of quercetin. METHODS: OA was induced in C57BL/6 mice via destabilization of the medial meniscus (DMM), with or without exposure to 20-nm polystyrene NPs (0.5 mg/mL in drinking water). For therapeutic intervention, quercetin (25 or 50 mg/kg) or indomethacin (3 mg/kg) was administered daily. Cartilage destruction was assessed by histology using the Osteoarthritis Research Society International (OARSI) scoring system, immunohistochemistry, and X-ray. In vitro, primary murine chondrocytes were treated with NPs and/or quercetin. Mechanisms were investigated using transmission electron microscopy, immunofluorescence, Western blot, organelle staining, and siRNA knockdown. RESULTS: NPs exposure significantly accelerated cartilage degradation and OA progression in DMM mice. Internalized NPs accumulated in chondrocyte lysosomes, inducing lysosomal membrane permeabilization (LMP), cathepsin B release, and subsequent NLRP3 inflammasome activation, leading to pyroptosis (evidenced by cleavage of gasdermin D N-terminal, GSDMD-N) and extracellular matrix loss. Quercetin restored lysosomal integrity, inhibited the LMP-NLRP3-pyroptosis axis in chondrocytes, and markedly attenuated NPs-aggravated cartilage destruction in vivo. CONCLUSION: This study identifies nanoplastics as novel environmental risk factors that act as pathological amplifiers in the context of osteoarthritis by inducing lysosomal destabilization-mediated pyroptosis in chondrocytes. Quercetin alleviates this pathological cascade by stabilizing lysosomes, highlighting its potential as a therapeutic agent against nanoplastics-exacerbated OA.