Membrane-targeted push-pull azobenzenes for the optical modulation of membrane potential

We introduce a family of membrane-targeted azobenzenes (MTs) with a push-pull character as a new tool for cell stimulation. These molecules are water soluble and spontaneously partition in the cell membrane. Upon light irradiation, they isomerize from trans to cis, changing the local charge distribution and thus stimulating the cell response. Specifically, MTs photoisomerization induces clear and reproducible depolarization. The most promising species, MTP2, was extensively studied. Time-resolved spectroscopy techniques provide insights into the excited state evolution and a complete understanding of its isomerization reaction. Molecular Dynamics simulations reveal the spontaneous and stable partitioning of the compound into the cellular membrane, without significant alterations to the bilayer thickness. MTP2 was tested in different cell types, including HEK293T cells, primary neurons, and cardiomyocytes, and a steady depolarization is always recorded. The observed membrane potential modulation in in-vitro models is attributed to the variation in membrane surface charge, resulting from the light-driven modulation of the MT dipole moment within the cell membrane. Additionally, a developed mathematical model successfully captures the temporal evolution of the membrane potential upon photostimulation. Despite being insufficient for triggering action potentials, the rapid light-induced depolarization holds potential applications, particularly in cardiac electrophysiology. Low-intensity optical stimulation with these modulators could influence cardiac electrical activity, demonstrating potential efficacy in destabilizing and terminating cardiac arrhythmias. We anticipate the MTs approach to find applications in neuroscience, biomedicine, and biophotonics, providing a tool for modulating cell physiology without genetic interventions.