Amelioration of the Rheumatoid Arthritis Microenvironment Using Celastrol-Loaded Silver-Modified Ceria Nanoparticles for Enhanced Treatment

Rheumatoid arthritis (RA) is characterized by elevated levels of reactive oxygen species (ROS) and a persistent inflammatory microenvironment dominated by pro-inflammatory M1 macrophages, both of which contribute to disease progression. To address these pathological features, we developed a core-shell nanoplatform consisting of silver-modified ceria nanoparticles (Ag-CeNP-PEG) loaded with celastrol (Cel), termed Ag-CeNP@Cel. This nanoplatform significantly enhances the water solubility of Cel and reduces its hepato-renal toxicity by enabling passive accumulation in inflamed joints through the extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS) effect. The Ag-CeNP-PEG platform synergistically combines with Cel to scavenge excess ROS and reprogram pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages, thereby mitigating inflammatory responses and improving the rheumatoid arthritis microenvironment (RAM). Ag-CeNP@Cel exhibited robust therapeutic efficacy and safety in preclinical models, presenting an innovative approach to RA treatment by integrating ROS elimination with macrophage modulation to ameliorate inflammatory microenvironment. This study underscores the potential of Ag-CeNP@Cel as a promising therapeutic strategy for RA management.