Modified proposomes as a novel intra-articular delivery approach for rheumatoid arthritis.

A novel intra-articular (IA) nanocarrier system for leflunomide (LEF) was developed using modified proposomes to enhance therapeutic efficacy in rheumatoid arthritis (RA). LEF was efficiently encapsulated within propylene glycol-based proposomes, which were sequentially functionalised with chitosan (CS) and hyaluronic acid (HA) to improve stability, bioadhesion and targeted delivery. The optimised nanoparticles exhibited a uniform nanoscale size, a zeta potential of -50.46 ± 6.4 mV, and a high entrapment efficiency of 94.12 ± 1.7%. In vitro release studies revealed a sustained LEF release profile from LEF-HA-proposomes over 84 h. In a Complete Freund's adjuvant (CFA)-induced RA rat model, IA administration of LEF-HA-proposomes resulted in marked therapeutic improvements (P˂0.05), including a 39.24% reduction in paw edoema, a 3.26-fold decrease in rheumatoid factor, a 3.47-fold reduction in TNF-α, and a 4.75-fold decline in IL-1β levels, accompanied by a 2.73-fold elevation in Nrf2 expression. Histopathological evaluation confirmed significant preservation of joint architecture and attenuation of synovial inflammation in the LEF-HA-proposomes group. Collectively, these findings highlight LEF-HA-proposomes as a promising IA nanocarrier platform for targeted RA therapy, offering prolonged drug retention, enhanced local anti-inflammatory efficacy, and minimised systemic toxicity compared with conventional oral treatments.