Abstract: Cannabidiol (CBD) holds promise for managing metabolic diseases, yet enhancing its oral bioavailability and efficacy remains challenging. To address this, we developed polymeric nanoparticles (NPs), using poly(lactic-co-glycolic acid) (PLGA), encapsulating CBD using nanoprecipitation, aiming to create an effective CBD-nanoformulation for metabolic disorder treatment. These NPs (135-265 nm) demonstrated high encapsulation efficiency (EE% = 100%) and sustained release kinetics. Their therapeutic potential was evaluated in an in vitro metabolic syndrome model employing sodium palmitate-induced HepG2 cells. Key assessment parameters included cell viability (MTT assay), glucose uptake, lipid accumulation (Oil Red O staining), triglycerides, cholesterol, HDL-c levels, and gene expression of metabolic regulators. Results showed an IC50 of 9.85 ug/mL for free CBD and 11.26 ug/mL for CBD-loaded NPs. CBD-loaded NPs significantly enhanced glucose uptake, reduced lipid content, lowered triglycerides and total cholesterol, and increased HDL-c levels compared to free CBD. Gene analysis indicated reduced gluconeogenesis via downregulation of PPARy, FOXO-1, PEPCK, and G6Pase and enhanced fatty acid oxidation through CPT-1 upregulation. These findings suggest that CBD-loaded NPs may serve as a novel therapeutic strategy for the management of metabolic disorders, warranting further in vivo studies.

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