LAUSR

Strategies to electrically stimulate cells with subcellular resolution while minimizing invasiveness have the potential to revolutionize bioelectronic research. Optoelectronics, and particularly silicon nanowires (SiNWs), offer such capabilities due to their biocompatibility, spontaneous internalization, and photoelectrochemical properties. However, the underlying mechanisms by which SiNWs can optically induce intracellular calcium transients remain unclear. In this study, we mechanistically investigated these mechanisms. First, by depleting intracellular calcium stores, we demonstrated that intracellular, rather than extracellular, calcium is the source of optically induced calcium transients. Thereafter, to decouple the photothermal and photoelectrochemical contributions, we used intrinsic, photoanodic (n–i–p), or photocathodic (p–i–n) SiNWs. Our data shows that both photoanodic and photocathodic interfaces generated more significant calcium responses than the pure photothermal effect. For the photoelectrochemical response, reactive oxygen species (ROS) were found to dominate the photoanodic response, offering a potential strategy to tune oxidative stress responses. On the other hand, the photocathodic response modulated intracellular calcium via voltage-gated and calcium-sensitive channels of intracellular organelles, as evidenced by pharmacological inhibition of key organelles and signaling pathways. This work provides mechanistic insight into SiNW-mediated intracellular modulation, offering fundamental knowledge for the development of SiNW-based, leadless optoelectronic systems that enable precise and cell-specific interrogation within 3D biological constructs. These findings enable the application of safe, efficient, and spatially precise intracellular bioelectric modulation with enhanced subcellular resolution.