Targeted nanosome delivery of TPCA-1 for modulating inflammation in a mouse model of post-traumatic osteoarthritis

Inflammation plays a significant role in the pathogenesis of knee post-traumatic osteoarthritis (PTOA) characterized by damage to cartilage and surrounding tissues that results in loss of physiological function. This inflammation is mainly regulated by NF-κB pathway. The TPCA-1 can inhibit IκB kinase (IKK) β in NF-κB pathway. Here, we optimized the delivery of TPCA-1 to the damaged knee joint via targeted nanosomes and examined its effects in a mouse model of PTOA. PTOA was induced in mice through a modified cyclic mechanical loading method. Mice were divided into groups receiving vehicle, TPCA-1 solution, or TPCA-1-loaded nanosomes. A concentration of 100 μM TPCA-1 was used based on preliminary studies. Control groups included untreated and vehicle-treated animals. Treatment efficacy was assessed using in vivo imaging, serum biochemical assays, gene expression analysis of cartilage tissues, histopathology, and behavioral analysis. Mechanical loading induced significant knee joint damage in the model. TPCA-1 nanosomes notably attenuated the adverse effects of loading, outperforming both the vehicle and TPCA-1-solution in reducing inflammation. Notably, serum levels of total NO and LDH were significantly lower in the TPCA-1-nanosome group. Inflammation, as indicated by MMP13 and IL1β gene expression, was substantially reduced. Enhanced cartilage preservation and function were confirmed through IVIS imaging, histological assessments, and improved behavior metrics. The targeted delivery of TPCA-1 via nanosomes effectively inhibits the NF-κB pathway, leading to significant reductions in inflammation and cartilage damage in a PTOA mouse model. This strategy demonstrates potential as a therapeutic intervention for managing inflammation and preserving joint health in osteoarthritis.