Well-Defined Nanoscopic Embedded Therapeutics Nystro€m and Wooley stealth characteristics and/or direct their interactions with biological receptors. The nanoscopic dimensions allow for extended biological circulation and provide a framework for conjugation of imaging agents to track delivery to diseased site(s). Incorporating such multiple functions is complicated, requiring exquisite chemical control during production and rigorous characterization studies to confirm the composi- tions, structures, properties, and performance. Direct linkage to a particular disease is necessary to tune the chemical, physical, and morphological features to gain access to the disease site and deliver the cargo appropriately, for exam- ple, extravascular, intracellular, and so forth. Nanomedicine is a rapidly evolving field, for which poly- mer building blocks are proving useful for the construction of sophisticated devices, theranostics, that provide en- hanced diagnostic imaging and treatment of disease. We have special interests in the study of nanoscopic objects that are designed for treatment of lung infectious diseases, urinary tract infections, acute lung injury, and cancer. Our nanomedicine devices are derived from macromolecules that have well-defined compositions, structures, and topol- ogies, allowing for programmed assembly into nanostruc- tures having controlled sizes, shapes, and morphologies. The evolution of nanostructured materials from relatively simple overall shapes and internal morphologies to those of increasing complexity is driving the development of synthetic methodologies that allow for the preparation of increas- ingly complex nanomedicine devices. Moreover, the inclu- sion of functional units within selective compartments/ domains is of great importance to create (multi)functional materials. Combinations of controlled radical and ring- opening polymerizations, chemical transformations, and su- pramolecular assembly are employed to construct such materials as functional entities. We employ a variety of multi- functional monomers, together with selective polymeriza- tion chemistries, to afford regiochemically functionalized poly- mers, and then further conduct supramolecular assembly processes in water, often together with chemical transfor- mations, to afford discrete nanoscopic objects within aqu- eous solutions. This approach has similarities to the processes of nature, whereby small molecules (amino acids, nucleic acids, saccharides) are linked into polymers (proteins, DNA/RNA, polysaccharides, respectively) and then those polymers fold into three-dimensional conformations that can lead to nanoscopic functional entities. This Account will highlight our work over several years to tune the assembly of unique nanostructures, with examples of how their com- positions, structures, dimensions, and morphologies can 970 ’ ACCOUNTS OF CHEMICAL RESEARCH ’ 969–978 ’ 2011 ’ Vol. 44, No. 10 tune their performance as theranostic agents for the treat- ment of infectious diseases and cancer. Tuning the Biological Interactions and Biodistribution As indicated by their name, theranostic nanoparticle sys- tems (TNPs) are designed to fulfill two objectives: therapeutic delivery and diagnostic imaging. Parameters such as the biodistribution (BioD), pharmacokinetics (PK), and pharma- codynamics (PD) are inherently different between drug delivery systems (DDS) and imaging systems. Nanoparticles for drug delivery typically exhibit extended blood circulation times in order to increase plasma concentration of the pharmacologically active substance, and also to exploit fully the enhanced permeation and retention (EPR) effect or ligand-mediated targeting, to reach further increases in local drug concentrations at disease sites. On the other hand, nanoparticulate imaging agents often require a different set of BioD, PK, and PD properties to operate with optimized signal to background. Nanoscopic imaging agents are ad- ministered to increase the signal-to-noise ratio in a specific tissue and allow for a diagnostic image to be obtained. In the case where the nanoparticle imaging agent is combined with an “active” targeting ligand, the circulation half-life of the construct becomes a critical parameter. In this setting, a longer circulation will allow for accumulation (via more circulation passes) at the target, but will require that the nanoparticle ultimately clears in order to reduce background (concentration) in the circulating blood to provide contrast. For successful realization of functional TNPs, this means that these parameters of the device must compromise between the optimum for drug delivery and that for diagnostic imaging, which in turn requires flexible chemical synthesis to systematically tailor the size, shape, charge, placement of targeting ligands, degradation, drug loading and release kinetics, and so forth. In this context, shell cross-linked knedel-like nanoparti- cles (SCKs) are versatile constructs for which a substantial body of work has been performed to establish protocols for controlling such parameters that are fundamental for nano- medical research, in general, and theranostic applications, in particular. In 2008, the Wooley lab developed a protocol for designing SCK nanoparticles that exhibited tailored PK and BioD.1 The foundation for preparing these cross-linked NPs was to utilize an amphiphilic block copolymer scaffold with specific hydrophilic/hydrophobic ratios to render SCKs with controlled core and shell dimensions (Figure 1). To tailor the BioD and PK characteristics, these block copolymers were