<p>Background </p><p>NOD-like receptors (NLRs) and inflammasome complexes play critical roles in the neuroinflammatory responses triggered by chronic ethanol exposure. We previously demonstrated that mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) attenuated binge-like alcohol consumption-induced NLRP3 inflammasome activation in the adolescent hippocampus; however, their broader effects on additional NLR pathways and brain regions remained unclear. </p><p>Methods and Results </p><p>This study investigates the therapeutic potential of intravenously administered adipose-derived MSC-EVs (20&#xa0;µg/dose every 10 days) in a murine model of chronic alcoholism, established by providing 10% ethanol in drinking water for three months. We specifically focused on changes in the expression of inflammasome sensor genes (<i>Nlrp3</i>, <i>Nlrc4</i>, <i>Nlrp1</i>, and <i>Aim2</i>) and downstream effector genes (<i>Casp-1</i>,<i> Casp-11/4</i>, <i>Il1b</i>, and <i>Il18</i>) across the prefrontal cortex, hippocampus, and striatum. qPCR analysis revealed that chronic ethanol exposure significantly upregulated the expression of the noted inflammasome-related genes in all three brain regions. MSC-EV treatment normalized the ethanol-induced overexpression of inflammasome sensor and downstream effector genes, suggesting the broad attenuation of inflammasome-driven neuroinflammatory responses. </p><p>Conclusions </p><p>These findings, together with our previous results, further expand our current understanding of MSC-EVs as a multifaceted therapy for ethanol-related neuropathology. This research underscores the capacity of MSC-EVs to simultaneously suppress multiple NLR inflammasome pathways in brain areas implicated in alcohol use-associated cognitive deficits and addictive behavior.</p>