The application of novel ultrathin iron sulphide nanosheets in the nanotherapy of post-traumatic osteoarthritis

Abstract

Post-traumatic osteoarthritis (PTOA) is a progressive joint disease characterised by cartilage degeneration and subchondral bone remodelling, in which persistent oxidative stress and inflammation jointly drive structural deterioration and functional loss. Most therapeutic strategies primarily alleviate symptoms or target single tissues, with limited efficacy in modifying disease progression. Here, we developed degradable ultrathin iron sulphide nanosheets (FeSNSs) and prepared a PEGylated therapeutic formulation (FeS-PEG) that concurrently protects articular cartilage and stabilises subchondral bone by alleviating oxidative-stress-associated joint damage in PTOA. The resulting FeS-PEG formulation exhibited favourable colloidal stability and pronounced ROS-scavenging activity. In vitro, FeS-PEG reduced intracellular ROS and lipid peroxidation in H2O2- and IL-1β-stimulated chondrocytes, restored antioxidant enzyme activity, attenuated COX-2/iNOS and pro-inflammatory cytokine expression, and preserved chondrocyte phenotype by promoting COL II expression while suppressing MMP3- and MMP13-mediated matrix degradation. Transcriptomic profiling further revealed that FeS-PEG reprogrammed IL-1β-induced PTOA-like gene expression, rebalancing extracellular matrix organisation, inflammatory signalling, and redox homeostasis. In an anterior cruciate ligament transection-induced PTOA rat model, intra-articular FeS-PEG administration significantly reduced cartilage erosion, OARSI histological scores, and local inflammation. Micro-CT revealed preserved subchondral bone microarchitecture with increased bone volume fraction and decreased trabecular separation, indicating inhibition of early maladaptive bone remodelling. Collectively, the findings establish FeS-PEG as a dual-functional, ROS-targeting nanotherapeutic platform that couples cartilage protection with subchondral bone preservation, offering a promising disease-modifying strategy for PTOA and broadening the potential applications of FeS-based nanomedicine in orthopaedics.