Optical Control of Intracellular Redox Balance in Cardiovascular Cells by Conjugated Semiconducting Polymers

In cell physiology, the term “redox homeostasis” refers to the balance between oxidizing and reducing agents and is recognized as a core concept governing the entire cell cycle. An imbalance in cellular redox status is intrinsically linked to the onset and progression of numerous diseases¹. Specifically, Intracellular Reactive Oxygen Species (ROS) concentration plays a crucial role in the control and fine tuning of several physiological functions, from cell proliferation to differentiation, from migration to metabolic activity, to specific functionalities². As a consequence, there has been a growing interest in the emerging field of 'redox medicine' over the past few years³.<br/>Currently available treatments to modulate the cell redox balance rely on the employment of chemically controlled methods. However, this strategy often fails to achieve accurate spatial and temporal control, is not reversible and is unsuitable for finely-tuned control of sub-cellular organelles. Employing optical excitation as a stimulus to precisely modulate intracellular ROS concentration at non- toxic levels offers the opportunity to overcome these limitations, but requires the development of novel, photoelectrochemically active transducers.<br/>To support the development of new tools for precise, non-toxic, non-invasive and on-demand modulation of intracellular ROS concentration it is therefore necessary to develop new biocompatible materials, characterized by highly tunable electrochemical efficiency and good stability in a biological environment⁴. Moreover, stimulation protocols should be as minimally invasive as possible.<br/>Here, we propose a novel strategy, based on the use of ad-hoc chemically functionalized semiconducting polymers, with enhanced opto-electrochemical properties^5,6. We investigate the phototransduction process, highlighting how photoelectrochemical reactions occurring at the polymer/electrolyte interface can modulate ROS concentration on-demand.<br/>We successfully employ extra- and intracellular delivery strategies, respectively based on polymer thin<br/>films and NPs, to achieve ROS increase within the <i>eu</i>stress dynamic range in relevant cardiovascular cell models. We demonstrate that photoelectrochemically active organic semiconductors developed in this work potentially satisfy all the requirements for innovative in-vivo redox-based therapies, potentially advancing clinical applications in the redox medicine field.<br/>So, we investigate the possibility to exploit photo-activated ROS to activate redox-dependent biochemical pathways with pivotal roles in cardiovascular cells, such as calcium dynamics, nitric oxide modulation, angiogenesis process^8,9.<br/>These results open up unexplored possibilities for wireless, geneless, and optically driven regenerative therapies in the cardiovascular domain, targeting the restoration of endothelial tissue functionality, the normalization of hypervascularization stages, and over a longer perspective the optical pacing of cardiac cells.<br/><br/><br/>References<br/><br/>1. H. Sies et al., J. Biol. Chem, (2014)<br/>2. M. Nitti et al., Antioxidants (2022)<br/>3. H. Sies et al., Nat Rev Mol Cell Biol. (2020)<br/>4. C. Bossio et al., Front. Bioeng. Biotechnol. (2018)<br/>5. M. Criado-Gonzalez et al., ACS Appl. Mater. Interfaces (2023)<br/>6. M. Criado-Gonzalez et al., Nano Letters (2024)<br/>7. G. Tullii, Nanoscale (2023)<br/>8. C. Ronchi, Advanced Science (2023)