Noninvasive magnetic resonance (MR) molecular imaging and targeted drug delivery systems, often referred to as theranostic agents, are being developed to enable improved detection, patient risk stratification, site-specific treatment, and longitudinal monitoring. 1 One example of these agents, a gadolinium-based perfluoro-carbon nanoparticle, has been used to detect, characterize, treat, and follow angiogenesis in preclinical models of cancer and atherosclerosis. Despite the preclinical success of this and related nanotechnology platforms, the recent discovery of nephrogenic systemic fibrosis (NSF), a serious and unexpected side effect of gadolinium blood pool agents observed in some patients with renal disease or following liver transplant, has cast a shadow on currently approved MR contrast agents. 2 Patients with NSF develop thickening of the skin and connective tissues that can inhibit arm and leg movements and even lead to bone fractures. Approximately 5% of patients experience a rapidly progressive course, which may result in death due to widespread fibrosis. The cause of NSF is unknown and there is no effective treatment of this condition. Although gadolinium has been the dominant paramagnetic metal for MR contrast agents, the issue of NSF has induced consideration of alternative approaches.Manganese was one of the first reported examples 3,4 of paramagnetic contrast material studied in cardiac and hepatic MRI because of its efficient R 1 enhancement. Similar to Ca 2+ and unlike the lanthanides, manganese is a natural cellular constituent, and often a cofactor for enzymes and receptors. Manganese blood pool agents, such as mangafodipir trisodium, have been approved as a hepatocyte-specific contrast agent with transient side-effects due to dechelation of manganese from the linear chelate. Nontargeted liposomal agents have included MnSO 4 3c or Mn-DTPA. 3d Release of Mn caused by disruption of the vesicles allowed MR detection of sites where the vesicles were non-specifically entrapped.Manganese(III)-labeled nanobialys (1) are a potential targeted MR theranostic nanoparticle produced by molecular self-assembly of amphiphilic branched polyethylenimine, which has a toroidal shape, tunable particle size, and low polydispersity. The "bialy" shape affords increased stability and presents kinetically stable, porphyrin coupled Mn(III) complexes directly to the surrounding water. In a typical synthesis, commercially available branched polyethylenimines (MW = 10 kDa) are hydrophobically modified (nominal 55% conjugation of the 1° amine) with linoleic acid by activating the carboxylic acid groups with 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (1.2 equiv) and allowing the reaction overnight at ambient temperature. Supramolecular self-assembly of the amphiphilic polymer in anhydrous chloroform, assumes inverted micellar 5 structures (2) that are able to transfer a water soluble new candidate contrast agent Mn(III)-protoporphyrin chloride (Mn-PPC, 4) into chloroform. Synergistic self-assembly of the ag...