CCR2‐Guided T reg Exosome–Gas6 Hybrid Synergistically Reprograms Macrophage Inflammation and Immune Tolerance in Gouty Arthritis

ABSTRACT Gouty arthritis (GA) is a recurrent inflammatory joint disease initiated by monosodium urate (MSU) crystal deposition and driven by progressive immune dysregulation. The collapse of immune tolerance, together with persistent synovial inflammation and pathogenic cytokine imbalances, jointly exacerbates joint injury. Here, we design a bioresponsive therapeutic platform composed of regulatory T cell (T reg )‐derived exosomes co‐loaded with growth arrest‐specific protein 6 (Gas6), engineered to preferentially home to inflamed joints via CCR2‐guided chemotactic targeting. The two components of the hybrid—Gas6 and T reg exosomes—exert both independent and synergistic immunomodulatory effects. By mitigating inflammation and reprogramming the tissue environment toward a tolerogenic state, the system bridges innate and adaptive immunity to restore overall immune function. In an MSU‐induced murine GA model, this therapy not only alleviates key clinical symptoms, but also promotes the expansion of regulatory T cells and suppresses T H 17 responses, leading to restoration of a more tolerogenic immune balance. Together, our study presents a cell‐free, CCR2‐guided immunoengineering approach that achieves targeted delivery and coordinated immune reprogramming, offering a promising strategy for treating GA and other disorders associated with immune imbalance.