Enhanced Metabolic Syndrome Management Through Cannabidiol‐Loaded PLGA Nanoparticles: Development and In Vitro Evaluation

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 μg/mL for free CBD and 11.26 μg/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 PPARγ, 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.