Multifunctional Methotrexate-Laden Nanotherapy Modulates the Joint-Brain Axis and Attenuates Associated Neuroinflammation in an Experimental Model of Rheumatoid Arthritis

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by persistent synovial inflammation, cartilage erosion, and systemic manifestations, including cognitive and neuropsychiatric complications. Increasing evidence highlights the bidirectional interplay of the joint-brain axis between peripheral inflammation and central nervous system dysfunction as a critical contributor to RA pathogenesis. Current frontline treatments, such as methotrexate (M), face challenges, including poor bioavailability, off-target toxicity, and limited efficacy in addressing neuroinflammation. To address these limitations, we developed methotrexate-loaded tryptophan-Poly(lactic-co-glycolic acid)-glutathione nanomicelles (M-WPG NMs), an advanced enzyme- and pH-responsive drug delivery platform designed for targeted release at inflamed joints. In collagen-induced arthritis (CIA) models, M-WPG NMs demonstrated superior therapeutic efficacy by significantly reducing joint inflammation, downregulating pro-inflammatory cytokines, and preserving joint architecture. Additionally, M-WPG NMs attenuated microglial activation and mitigated associated neuroinflammation in chronic RA, offering dual modulation of both peripheral and central inflammatory responses. This multifunctional nanocarrier improves methotrexate delivery, enhances therapeutic outcomes, and addresses the often-overlooked neurological components of RA. Our findings support the application of M-WPG NMs as a next-generation nanomedicine for comprehensive RA management, capable of controlling disease progression while offering protection against RA-induced cognitive dysfunction.