A novel treatment modality for rheumatoid arthritis: Inflammation-targeted multifunctional metal-organic frameworks with synergistic phototherapy and chemotherapy.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with complex pathogenesis. Single chemotherapy struggles to eliminate the disease permanently and reduce the pain owing to drug resistance and inadequate delivery to target cells. This study developed hyaluronic acid (HA)-modified and methotrexate (MTX)-load metal-organic frameworks (denoted as FT-HA-MTX NPs), combining photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy to inhibit the progression of RA. In vitro experiments proved that the obtained NPs exhibited good biocompatibility and commendable photothermal conversion efficiency of 36.3 %. Additionally, they promoted ∙OH and O production via the Fenton reaction, which dramatically alleviated hypoxia and enhanced ROS generation, and induced substantial mortality in activated RAW 264.7 cells, with cell viability of 31.72 %. Cellular uptake and in vivo imaging confirmed that the modification of HA enabled the NPs to specifically target activated macrophage, ensured prolonged retention of NPs in inflamed synovial tissues, and reduced systemic toxicity. In vivo, after FT-HA-MTX NPs treatment with laser irradiation, the levels of TNF-α and IL-1β in the synovial tissue were reduced by approximately 50 % compared to those in the inflamed synovium, demonstrating a significant enhancement in the anti-inflammatory effect (p < 0.001). In conclusion, FT-HA-MTX NPs are promising inflammation-targeted multifunctional nanoparticles that combine PTT, PDT, and chemotherapy, thereby significantly inhibiting the progression of RA while reducing systemic toxicity.