Engineered microorganisms drive local metabolic reprogramming to Re-educate systemic immunity

Rheumatoid arthritis (RA) features chronic synovial inflammation and systemic immune disorders. Current treatments mainly rely on systemic immunosuppression, raising risks of infection and long-term immune injury. Local therapies reduce such risks but struggle to regulate systemic immunity. Emerging studies show the synovial immunometabolic microenvironment links local inflammation to systemic responses. Here, we developed a strategy based on chemically attenuated photosynthetic bacteria that couples lactate metabolism with photo-driven hydrogen production to achieve local metabolic reprogramming and systemic immune re-education. We screened a photosynthetic bacterial strain with high lactate metabolic capacity, which also exhibited enhanced hydrogen production. To ensure safety, bacteria were PEGylated to mask immunogenic moieties while preserving metabolic activity. Intra-articular injection disrupted pathological crosstalk and restored the Treg/Th17 balance locally. Circulating IL-6 levels decreased, restoring the systemic regulatory role of Tregs, thereby alleviating distant joint inflammation. These results demonstrate that local synovial metabolic reprogramming by engineered bacteria can induce systemic immune re-education, offering a conceptually new therapeutic strategy for treating autoimmune arthritis.