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Nanoparticle based cellular therapies hold great promise for clinical applications and medicinal use in human patients by allowing for targeted delivery of a personalized medicine payload to specific cells and tissues in a variety of disease states. The large surface to volume ratio of solid inorganic nanoparticles and the availability of facile surface functionalization chemistries with gold, gold-coated, and semi-conductor nanoparticles enables the design of delivery agents which can simultaneously carry a targeting molecule, such as an antibody or cell penetrating peptide (CPP), a short oligonucleotide for RNA interference or intracellular sensing, and a full gene for genetic therapy to correct aberrant protein function or cause apoptosis of cancer cells. The scope of applicability for nano-therapy technology is incalculable, however current understanding of the intracellular uptake and processing of nanomaterials-based therapeutics is limited and many facets of the cellular response to nanoparticle therapy are still in need of investigation. The goal of this dissertation work has been to elucidate the effects of nanoparticle-based therapeutics to ascertain the intracellular fate and processing of model nanomedicines by designing nanoparticle-bioconjugates capable of spatiotemporally reporting live intracellular uptake and processing events using fluorescence microscopy, and magnetic detection. The first chapter gives an introduction to nanoparticles and their use in biological applications, as well as detailing how they can be used as intracellular sensors. The second chapter investigates the ability to control therapeutic DNA cargo release from a gold nanoparticle in live cells using different appendage chemistries. The third chapter probes the intracellular environment experienced by the nanotherapeutic and discusses nano-induced effects to the intracellular environment. The fourth chapter investigates nanotherapy cellular uptake targeting using cell penetrating peptides, as probed by fluorescent quantum dots, to determine outcomes for a variety of naïve and drug resistant mammalian cell lines, include human lung, skin and brain cancers as well as rodent cancer model cell lines. The fifth chapter combines optical and magnetic analysis techniques to investigate multiplexed sensing with gold shelled iron oxide nanoparticles to investigate cellular uptake. And the last chapter summarizes the work and provides a discussion of the outlook for the work.