PROJECT SUMMARY/ABSTRACT Exosomes were originally thought of as the cellular “waste-disposal system.” It is now known that they are important for intercellular communication and contribute to the pathogenesis of several diseases including cancer, neurodegenerative disease, and autoimmunity. Once secreted from parental cells, exosomes can be: (a) captured by neighboring cells, and/or (b) released into the systemic circulation for uptake by distant tissues and organs. Thus, their effects are not only local but can have far reaching systemic consequences. For example, cancer invasion and metastasis are promoted by exosomes and their contents. Currently, no therapeutic strategies exploit pathological crosstalk between cells to interrupt disease progression; most therapies target intracellular signaling. The goal of this proposal is to design and synthesize RNA EXO-Codes that are selectively enriched in exosomes. These will be used to: (i) deliver therapeutic RNAs that will reprogram pathological exosomes in vitro and in vivo, and (ii) elucidate mechanisms of nucleic acid sorting to exosomes. Successful completion of this research will result in a platform of zip-code-like biomaterials capable of selectively loading therapeutic cargo into exosomes. This will lay the foundation for the development of a novel therapeutic strategy, based on the hijacking of exosomal sorting machinery, for treating diseases in which exosomes are pathological.