Since the late 1980s, researchers have prepared inorganic nanoparticles of many types - including elemental metals, metal oxides, metal sulfides, metal selenides, and metal tellurides - with excellent control over size and shape. Originally many researchers were primarily interested in exploring the quantum size effects predicted for such materials. Applications of inorganic nanomaterials initially centered on physics, optics, and engineering but have expanded to include biology. Many current nanomaterials can serve as biochemical sensors, contrast agents in cellular or tissue imaging, drug delivery vehicles, or even as therapeutics.In this Account we emphasize that the understanding of how nanomaterials will function in a biological system relies on the knowledge of the interface between biological systems and nanomaterials, the nano-bio interface. Gold nanoparticles can serve as excellent standards to understand more general features of the nano-bio interface because of its many advantages over other inorganic materials. The bulk material is chemically inert, and well-established synthetic methods allow researchers to control its size, shape, and surface chemistry. Gold's background concentration in biological systems is low, which makes it relatively easy to measure it at the part-per-billion level or lower in water. In addition, the large electron density of gold enables relatively simple electron microscopic experiments to localize it within thin sections of cells or tissue. Finally, gold's brilliant optical properties at the nanoscale are tunable with size, shape, and aggregation state and enable many of the promising chemical sensing, imaging, and therapeutic applications.Basic experiments with gold nanoparticles and cells include measuring the toxicity of the particles to cells in in vitro experiments. The species other than gold in the nanoparticle solution can be responsible for the apparent toxicity at a particular dose. Once the identity of the toxic agent in nanoparticle solutions is known, researchers can employ strategies to mitigate toxicity. For example, the surfactant used at high concentration in the synthesis (0.1 M) of gold nanorods remains on their surface in the form of a bilayer and can be toxic to certain cells at 200 nM concentrations. Several strategies can alleviate the toxic response. Polyelectrolyte layer-by-layer wrapping can cover up the surfactant bilayer, or researchers can exchange the surfactant with chemically similar molecules. Researchers can also replace the surfactant with a biocompatible thiol or use a polymerizable surfactant that can be "stitched" onto the nanorods and reduce its lability. In all these cases, however, proteins or other molecules from the cellular media cover the engineered surface of the nanoparticles, which can drastically change the charges and functional groups on the nanoparticle surface.
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