Inflammation specific environment activated methotrexate-loaded nanomedicine to treat rheumatoid arthritis by immune environment reconstruction

Rheumatoid arthritis (RA), as an autoimmune inflammatory disease, is featured by enhanced vascular permeability, irreversible cartilage destroys and bone erosion. Although the pathogenesis of RA is still unclear, the immune environment, particularly the lymphatic system, which is instrumental to immune cell surveillance and interstitial fluid balance, plays vital roles in the process of RA. Herein, an inflammation specific environment activated methotrexate-encapsulated nanomedicine (MTX@NPs) was constructed for RA treatment, which accumulated in inflamed joints, and released MTX in the specific RA microenvironment. Notably, MTX@NPs could regulate the immune environment including reducing the expressions of inflammatory cytokines of macrophages and the inflammatory level of lymphatic epithelial cells (LECs), and ameliorating the lymphatic vessel contraction and drainage. In vitro and In vivo studies illustrated that MTX@NPs exhibited a high RA therapeutic efficacy and insignificant systemic toxicity owing to the suppression of the inflammation response and the improved lymphatic functions of RA joints. It suggests that the nanomedicine paves a potential way to the clinical practice of autoimmune diseases treatments via the regulation of immune environment and lymphatic functions. STATEMENT OF SIGNIFICANCE: Although 1.0% of the population in the world suffers from rheumatoid arthritis (RA), the pathogenesis of RA is still unclear and the therapeutic effect of the first-line clinical drugs is relatively low. Herein, we propose a specific RA-microenvironment triggered nanomedicine (MTX@NPs), which enhances RA treatment of a first-line antirheumatic drug (methotrexate, MTX) by immune environment reconstruction. The nanomedicine exhibits RA joints accumulation by EPR effect, and releases MTX under the specific RA environment, leading to the dramatical drop of M1-type macrophages and acceleration of lymphatic vessel contraction and drainage. Finally, the inflammatory cytokines in RA immune environment are reduced sharply, indicating the outstanding therapeutic efficacy of MTX@NPs to RA.