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.