Immunomodulatory supramolecular hydrogel for rheumatoid arthritis management via adenosine A2A receptor-mediated macrophage remodeling

Synovial tissue infiltration by pro-inflammatory macrophages is a critical factor in the pathogenesis of rheumatoid arthritis (RA), correlating strongly with high disease activity scores in affected joints and often lead to progressive joint damage and disability. Methotrexate (MTX) is the frontline therapeutic drug for RA, but its efficacy is hampered by short plasma half-life, reduced bioavailability, and severe adverse effects. To address these limitations, we developed an injectable polymer-nanomedicine supramolecular hydrogel (PNSH) with dynamic mechanical properties and morphology tailored for intra-articular administration and sustained drug release with minimized off-target toxicity. The hydrogel was assembled from MTX-loaded polymeric nanoparticles chemically conjugated with partially oxidized glucomannan. <i>In vitro</i> and <i>in vivo</i> studies demonstrate that PNSH exhibits low cytotoxicity and superior biocompatibility. It supports the sustained release of MTX, which promotes M1 macrophage remodeling towards the M2 macrophage via switching IRF5 and IRF8 to IRF3 and IRF4 through the adenosine A2A receptor (A2AR) signaling pathway. In a rat arthritis model, PNSH effectively mitigated tissue-damaging inflammation and restored the articular immune homeostasis, thereby inhibiting arthritis progression. Notably, PNSH also upregulated CD73 and A2AR, key components of the extracellular purinergic signaling pathway, promoted the transcriptional expression of IRF3 and IRF4, and significantly decreased the transcriptional expression of IRF5 and IRF8, driving macrophage re-polarization towards M2 phenotype. These findings suggest that PNSH has the potential to serve as a novel drug delivery system for regulating inflammation and treating RA.