Bioinspired exosome-SiO₂ nanohybrid therapeutic for rheumatoid arthritis treatment

Objective: Due to their anti-inflammatory and immunomodulatory capabilities, adipose-derived stem cells (ADSC) are currently considered a promising option for the management of rheumatoid arthritis (RA). To tackle the problems of immunogenicity and tumorigenicity linked to the direct use of cells, current research is focused on the development of effective nanomedicines utilizing ADSC-derived exosomes (ADSC-EXO) for cell-free regenerative medicine. Methods: Methotrexate (MTX) was loaded into mesoporous silica through physical adsorption to produce SiO₂-MTX, with subsequent incorporation into ADSC-EXO via ultrasonication to produce AE@SiO₂-MTX. Particle size, surface charge, and stability were characterized using dynamic light scattering (DLS) and zeta potential analysis. In vitro, the effects of the nanomaterials were evaluated by assessing the inverse polarization effect of AE@SiO₂-MTX on RAW264.7 macrophages, as well as on the migration and invasion capabilities of fibroblast-like synovial cells (FLS). In vivo, targeting and therapeutic effects on joint inflammation were examined using adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) mouse models. Results: The AE@SiO₂-MTX demonstrated sustained drug release, high biocompatibility, and rapid cellular internalization. In vitro, the delivery system alleviated chronic inflammation by inducing macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, as well as suppressing FLS migration and invasion. In vivo studies revealed that administration of ADSC-EXO outperformed ADSC transplantation in alleviating RA symptoms. Intravenously delivered AE@SiO₂-MTX exhibited targeted accumulation in inflamed joints, significantly reducing joint swelling, synovial hyperplasia, and bone/cartilage degradation in CIA model mice. Conclusions: The findings show that AE@SiO₂-MTX is a robust cell-free therapeutic platform for RA management. Synergy between the immunomodulatory properties of ADSC-EXO and MTX controlled release, this system can overcome the limitations of conventional cell therapies and achieve targeted anti-inflammatory and tissue-protective effects. This strategy offers a promising translational avenue for RA treatment.