Project Summary/Abstract The ability of cells to efficiently communicate across organismal-level distances and difficult-to-surmount biological barriers is one of the most important fundamental phenomena in biology. A vast body of literature has revealed that such cell-to-cell communication is mediated via membrane-enclosed particles called extracellular vesicles, which are released by cells into their surroundings and contain lipids, ligands, nucleic acids, and proteins. Such extracellular vesicles represent one of the only natural non-viral structures by means of which “source” cells can reprogram the genetics and fate of “target” cells, and as such, they are implicated not only in the regulation of nearly every cellular process but also in the development of nearly every tissue within the human body. Moreover, these vesicles play essential roles in various disease states and pathological conditions, including cancer progression, neurodegeneration, musculoskeletal disorders, cardiovascular degradation, metabolic syndromes, and wound healing. Given their ubiquity and crucial biological roles, extracellular vesicles hold great promise for clinical diagnostics and therapeutics, but to date, such applications have been hindered by key challenges associated with 1) fundamentally understanding extracellular vesicle formation in source cells, 2) loading extracellular vesicles with biomolecular cargo in high yield, 3) controllably regulating extracellular vesicle production with external stimuli, 4) delivering extracellular vesicles to target cells over tissue-relevant length scales, 5) maintaining the long-term biological activity of extracellular vesicle-internalized cargo, and 6) implementing extracellular vesicle-based treatment strategies in living animals. Herein, by drawing inspiration from proteins and structures found in cephalopod skin cells and leveraging the technical foundation established for cephalopod-inspired bioelectronic devices, we propose to solve all of the scientific and technological challenges currently impeding clinical applications of extracellular vesicles. The envisioned research plan involves 1) validating electrical techniques for controlling the release of extracellular vesicles from genetically engineered cells interfaced with different bioelectronic devices and platforms, 2) developing strategies for remotely and wirelessly controlling the release of biomolecular cargo-loaded extracellular vesicles from engineered cells interfaced into implantable bioelectronic systems, and 3) demonstrating that remotely controlled release of clinically valuable cargo-loaded extracellular vesicles by implanted bioelectronic system-integrated source cells can guide target cell fate and tissue development in living animals. Altogether, the successful completion of the proposed work will enable harnessing of extracellular vesicle-mediated cell-to-cell communication pathway for the regulation of physiological processes and will thus furnish transformative opportunities for developing unprecedented next generation diagnostic and therapeutic technologies.

Project Narrative The communication of cells over organismal-level distances and across difficult-to-surmount biological barriers is mediated by membrane-enclosed particles known as extracellular vesicles and constitutes one of the most important fundamental phenomena in biology. To date, surprisingly few technologies capable of controlling the formation, release, and delivery of extracellular vesicles have been developed, and these technologies possess significant technical limitations, inadequate key figures of merit, and lack viable paths to clinically-relevant applications. The proposed research seeks to develop a powerful and generalizable methodology for electrically controlling extracellular vesicle-mediated cell-cell communication and to leverage this methodology for guiding cell fate and directing tissue development in living animals.