Sesti Valentina, Magni Arianna, Moschetta Matteo, Florindi Chiara, Pfeffer Marlene E, DiFrancesco Mattia Lorenzo, Guizzardi Michele, Folpini Giulia, Sala Luca, Ritacca Alessandra Gilda, Campanelli Beatrice, Moretti Paola, Paternò Giuseppe Maria, Maragliano Luca, Tommasini Matteo, Lodola Francesco, Colombo Elisabetta, Benfenati Fabio, Bertarelli Chiara, Lanzani Guglielmo
Department of Chemistry, Materials and Chemical Engineering, "Giulio Natta" Politecnico di Milano, Milano, 20133, Italy.
Center for Nanoscience and Technology, Istituto Italiano di Tecnologia, Milano, 20134, Italy.
Light Sci Appl. 2025 Jan 1;14(1):8. doi: 10.1038/s41377-024-01669-x.
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.
我们引入了一类具有推拉特性的膜靶向偶氮苯（MTs），作为一种细胞刺激的新工具。这些分子可溶于水，并能自发地分配到细胞膜中。在光照下，它们从反式异构化为顺式，改变局部电荷分布，从而刺激细胞反应。具体而言，MTs的光异构化会引起清晰且可重复的去极化。对最有前景的物种MTP2进行了广泛研究。时间分辨光谱技术有助于深入了解激发态的演化，并全面理解其异构化反应。分子动力学模拟揭示了该化合物在细胞膜中的自发稳定分配，且不会显著改变双层膜的厚度。MTP2在包括HEK293T细胞、原代神经元和心肌细胞在内的不同细胞类型中进行了测试，始终记录到稳定的去极化现象。在体外模型中观察到的膜电位调制归因于膜表面电荷的变化，这是由细胞膜内MT偶极矩的光驱动调制引起的。此外，一个开发的数学模型成功地捕捉了光刺激后膜电位的时间演化。尽管不足以触发动作电位，但快速的光诱导去极化具有潜在应用，特别是在心脏电生理学中。用这些调节剂进行低强度光刺激可能会影响心脏电活动，在使心律失常失稳和终止方面显示出潜在疗效。我们预计MTs方法将在神经科学、生物医学和生物光子学中找到应用，为在不进行基因干预的情况下调节细胞生理学提供一种工具。
