https://www.selleckchem.com/products/urmc-099.html Amiodarone (AM) is a highly efficient drug for arrhythmias treatment, but its extra-cardiac adverse effects offset its therapeutic efficacy. Nanoparticles (NPs)-based delivery system could provide a strategy to allow sustained delivery of AM to the myocardium and reduction of adverse effects. The primary purpose was to develop AM-loaded NPs and explore their ameliorative effects versus off-target toxicities. Polymeric NPs were prepared using poly lactic-co-glycolic acid and their physicochemical properties were characterized. Animal studies were conducted using a rat model to compare exposure to AM versus that of the AM-loaded NPs. Biochemical evaluation of liver enzymes, lipid profile, and thyroid hormones was achieved. Besides, histopathological changes in liver and lung were studied. Under optimal experimental conditions, the AM-loaded NPs had a size of 186.90nm and a negative zeta potential (-14.67mV). Biochemical evaluation of AM-treated animal group showed a significant increase in cholesterol, TG, LDL, T4, and TSH levels (ρ<0.05). Remarkably, the AM-treated group exhibited a significant increase of liver enzymes (ρ<0.05) coupled with an obvious change in liver architecture. The AM-loaded NPs displayed a reduction of liver damage and enzyme levels. Lung sections of the AM-treated group demonstrated thickening of interalveolar septa, mononuclear cellular infiltration with congested blood vessels, and heavy collagenous fibers deposition. Conversely, less cellular infiltration and septal thickening were observed in the animal lungs treated with the AM-loaded NPs-treated. Our findings demonstrate the competence of the AM-loaded NPs to open several exciting avenues for evading the AM-induced off-target toxicities. Our findings demonstrate the competence of the AM-loaded NPs to open several exciting avenues for evading the AM-induced off-target toxicities. This study aimed to explore the therapeutic effects of amnio