Inflammatory microenvironment activation-targeted self-delivery nanomedicine for effective rheumatoid arthritis treatment

• SDNs can effectively avoid carrier-induced toxicity and immunogenicity. • Nanosized SDNs (DT@PEGT-NPs) can enhance efficacy and reduce side effects. • The principle of drug self-assembly of SDNs was deeply explained. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Current clinical therapies are still limited to disease-improving antirheumatic drugs, which can cause severe side effects in patients when taken for long periods. To address these challenges, an inflammatory microenvironment activation-targeted self-delivery nanomedicine (DT@PEGT-NPs) was designed. Methotrexate (MTX) and dexamethasone (DEX) were co-assembled to form nanoparticles (DT-NPs), which were then further assembled with polyethylene glycol (PEG)-covalently modified MTX to form a protective shell (PEGT). Based on the characteristics of the RA microenvironment, this self-delivery nanomedicine can accumulate at the site of inflammation through passive targeting. Simultaneously, the protective shell is shed in the weakly acidic inflammatory microenvironment of RA, enhancing drug self-targeting and uptake by inflammatory cells. The DT@PEGT-NPs effectively alleviated RA in vitro and in vivo , demonstrating a high therapeutic index and low systemic toxicity, and significantly reduced the swelling and inflammation in rats with collagen-induced arthritis (CIA). The cartilage morphology in DT@PEGT-NPs-treated rats remained intact, indicating their therapeutic effects in alleviating arthritic cartilage damage. By combining passive and active targeting, such self-delivered nanomedicines, activated by the inflammatory microenvironment, will open new avenues for better understanding the pathogenesis and therapeutic mechanisms of RA, contributing to the further development of RA therapeutics.