Abstract: Precise spatiotemporal control of ligand delivery into intact cells, organs, and organisms is important for the time resolved and causal analysis of the functions of neurotransmitters, neuromodulators, and hormones in the operation of complex biological systems, such as the brain. Over the past several decades, some success has been achieved in uncaging several small molecules through the attachment of photolabile chemical groups, which block the bioactivity of the molecule in the absence of light and release a bioactive molecule upon UV light irradiation. However, such photochemical uncaging modifications are difficult to develop for small molecules, and are nearly impossible for large molecules whose active sites are often too large to be blocked by the addition of chemical groups. In addition, caged molecules often exert leak bioactivity even before light delivery, and the use of UV light can be damaging to cellular components;as a result, despite proven utility in vitro, uncaging has been little used in vivo to study intact biological systems. Here, I will describe a novel strategy capable of uncaging arbitrary bioactive molecules and peptides with millisecond time scale resolution, using visible light safe for in vivo use. I will use computational protein and DNA design to construct light controllable 'NanoRobots', and use these NanoRobots to uncage a variety of molecules, peptides, and proteins in the intact organ systems. Such a strategy has the potential to revolutionize the study of ligand functions with unprecedented spatiotemporal precision, opening up new frontiers in basic molecular and systems neuroscience, pharmaceutical development, and side effect assessment. Public Health Relevance: The ability to deliver compounds and drugs with high spatiotemporal precision will drastically advance our understanding of the functions of neurotransmitters and neuromodulators in the nervous system. Here, I describe a novel strategy capable of delivering arbitrary bioactive molecules, peptides with millisecond time resolution, using a light controllabl NanoRobot.
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