Iron overload (IO) is one of the most common genetic diseases in the U.S. but individuals with the condition typically exhibit few symptoms in the early stages and are often unaware of their condition until it has already progressed to a dangerous level. Untreated, IO can induce cirrhosis and increase risk of liver cancer, cause arthritis, or lead to impotence. Recent studies have furthermore consistently demonstrated the presence of excess iron in the brains of Alzheimer and Parkinson’s disease patients. For treating acquired IO, Deferoxamine (DFO) is one of the few FDA-approved drugs available, but has been limited by toxicity issues and short circulation times. Furthermore, DFO is also currently unable to efficiently target the large pool of iron in the liver where a vast majority of excess iron is stored in the macrophages. In spite of these observations, surprisingly little work has focused on investigating the relationship between targeting of the liver, iron chelation efficacy in vivo, and the need to develop bio-responsive materials for chelating excess iron (termed nanochelators) and promoting iron-chelate excretion from the body. Since iron-mediated generation of highly toxic Reactive Oxygen Species (ROS) plays a major role in the process leading to IO-related diseases, my laboratory has been looking into design of ROS-responsive nanochelators to deliver DFO. Compared to free DFO, bio-responsive nanochelators did not induce cytotoxicity in cells nor display signs of acute toxicity in mice at therapeutic doses administered. Importantly, bio-responsive nanochelators returned systemic and liver iron concentration of IO mice to normal, and improved total renal and fecal elimination of iron-bound chelates.