PROJECT SUMMARY/ABSTRACT Iron overload, best represented by hereditary hemochromatosis (primary/genetic iron overload) and transfusional hemoglobinopathy (secondary/acquired iron overload), is a well-defined risk factor for several critical diseases, including heart failure, liver cirrhosis, arthritis, diabetes and neurodegenerative diseases. Iron chelators are clinically used to reduce iron burden, but the use of chelators is limited by a number of significant side effects, including hypotension, tachycardia, agranulocytosis, neutropenia, ocular/auditory toxicities, loss of essential nutrients, musculoskeletal-joint pains, gastrointestinal bleeding, hepatic fibrosis and renal failure. Considering tens of millions of people affected by various types of iron overload disorders, there are urgent needs for a new therapeutic strategy to minimize unwanted adverse effects of chelators by controlling the fate of iron-chelator complex in the body. The hypothesis guiding this study is that iron chelators coated onto size- and surface-modified nanoparticles (“nanochelators”) will collect excess iron from various body compartments, and the iron-chelator-nanoparticle complexes will be exclusively cleared by two major excretion pathways: into the urinary bladder by renal excretion and into the gallbladder/gut by biliary excretion depending on the size and surface properties of nanoparticles. The specific aims of this study are focused on 1) developing multifunctional chelator-coated urine-targeted nanoparticles (UNPs) to effectively harvest circulating and labile iron and dispose the iron-UNP complex by urinary excretion, 2) engineering surface-modified, chelator-coated bile-targeted nanoparticles (BNPs) to dispose excess iron exclusively by the biliary secretion pathway, 3) characterizing the in vivo pharmacokinetics and pharmacodynamics of developed nanochelators in iron disposal using clinically-relevant mouse and rat models of iron overload, and 4) evaluating the therapeutic efficacy of nanochelators in the amelioration of physiological complications associated with iron overload disorders. Overall, this strategy provides a safe and effective method with increased benefit/risk ratios of iron chelators to support therapeutic benefits over numerous iron overload disorders by a combination of nanotechnology and transgenic animal models of iron overload. Furthermore, the idea of “targeted clearance” can be tested for the facilitated elimination of other toxic substances, such as heavy metals and drugs of abuse, from the body. By addressing these questions, we hope to both identify novel therapeutic approaches and improve clinical outcomes.