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Gout arthritis (GA) is a painful inflammatory disease in response to monosodium urate (MSU) crystals in the joints. 15deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a natural activator of PPAR-γ with analgesic, anti-inflammatory, and pro-resolution properties. Thus, we aimed to evaluate the effect and mechanisms of action of 15d-PGJ2 nanocapsules (NC) in the model of GA in mice, since a reduction of 33-fold in the dose of 15d-PGJ2 has been reported. Mice were treated with 15d-PGJ2-loaded NC, inert NC, free 15d-PGJ2 (without NC), or 15d-PGJ2-loaded NC+ GW9662, a PPAR-γ inhibitor. We show that 15d-PGJ2-loaded NC provided analgesic effect in a dose that the free 15d-PGJ2 failed to inhibiting pain and inflammation. Hence, 15d-PGJ2-loaded NC reduced MSU-induced IL-1β, TNF-α, IL-6, IL-17, and IL-33 release and oxidative stress. Also, 15d-PGJ2-loaded NC decreased the maturation of IL-1β in LPS-primed BMDM triggered by MSU. Further, 15d-PGJ2-loaded NC decreased the expression of the components of the inflammasome Nlrp3, Asc, and Pro-caspase-1, as consequence of inhibiting NF-κB activation. All effects were PPAR-γ-sensitive. Therefore, we demonstrated that 15d-PGJ2-loaded NC present analgesic and anti-inflammatory properties in a PPAR-γ-dependent manner inhibiting IL-1β release and NF-κB activation in GA. Concluding, 15d-PGJ2-loaded NC ameliorates MSU-induced GA in a PPAR-γ-sensitive manner. [ABSTRACT FROM AUTHOR]