To test this hypothesis, we formulated PLGA ((poly(lactic-co-glycolic acid))-encapsulated rimonabant nanoparticles (Rimo-NPs) and demonstrated that they effectively inhibit hepatic CB1R and improve obesity-induced hepatic steatosis and insulin resistance without any apparent neuropsychiatric side effects. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.