AbstractGout arthritis (GA) is a painful inflammatory disease in response to monosodium urate (MSU) crystals in the joints. 15deoxy-Δ^12,14-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.