Biomimetic M2 exosome-based dual-drug nanoplatform for combined immunomodulation and bone protection in rheumatoid arthritis.

The current treatment of rheumatoid arthritis (RA) remains limited by severe drug-associated side effects and poor suppression of bone erosion. Herein, we report the development of biomimetic nanoparticles (CEC NPs) that co-deliver celecoxib (CXB) and the lysine-specific demethylase 1 (LSD1) inhibitor CC-90011 via M2 macrophage-derived exosomes (M2 Exos), thereby integrating targeted delivery with innovative multi-mechanistic therapeutic strategies. The M2 Exos enable innate homing to inflamed synovium and osteoclast-rich lesions, while ensuring efficient intracellular delivery. CEC NPs combined repolarize macrophages from the M1 to M2 phenotype, suppress fibroblast-like synoviocyte activation, and critically inhibit bone erosion by blocking the LSD1-NFATc1 signaling pathway in the osteoclast. Collectively, these effects result in potent anti-inflammatory and osteoprotective outcomes. Notably, we identified CC-90011 as a previously unrecognized anti-erosive agent to directly suppress bone erosion in RA treatment. In a collagen-induced arthritis (CIA) model, CEC NPs markedly outperform monotherapies, with pronounced reduction in joint swelling, cartilage degradation, and bone erosion, without systemic toxicity. This work introduces an M2 Exo-based dual-drug delivery system as a versatile strategy for multi-mechanistic modulation of inflammation and bone destruction, offering a promising paradigm that could be extended to other inflammatory and autoimmune bone disorders.