Rewiring Intercellular Communication with Self-Assembling Nanofibers.

Abstract

Intercellular electrical coupling mediated by gap junctions plays a central role in signal transmission in many biological systems. Its disruption contributes to cardiac and neurological disorders, as well as impaired wound healing and tumor progression. Restoring direct electrical communication between cells, however, remains challenging, particularly without genetic manipulation or the delivery of preformed devices across cellular membranes and interfaces. The small conjugated molecule DTTO (2,6-diphenyl-3,5-dimethyl-dithieno[3,2-b:2',3'-d]thiophene-4,4-dioxide) self-assembles inside living cells into supramolecular nanofibers, which can extend between neighboring cells and connect their cytoplasm. Here, we show that these fibers also establish functional electrical coupling between cells: dual patch clamp recordings demonstrate restored signal transmission even when native gap junctions are pharmacologically suppressed, while control experiments show that the recovered signal transmission does not result from nonspecific membrane poration associated with fibers crossing the membrane. Electrical characterization of DTTO fiber networks shows that these structures support charge transport, while humidity-dependent measurements, impedance spectroscopy, and equivalent circuit modeling show that the observed electrical response is shaped by ionic and interfacial contributions from the surrounding environment. Collectively, this work establishes intracellular DTTO self-assembly as a nongenetic strategy to create functional bioelectrical connections in situ and restore electrical communication in diseased and engineered tissues.