Semiconducting Polymer Nanoparticles Enable Light-Controlled Bidirectional Modulation of Nitric Oxide in Endothelial Cells

Endothelial-derived nitric oxide (& centerdot;NO) is a key signaling molecule in the vascular system, exerting concentration-dependent control over critical cellular functions such as angiogenesis, vascular tone, and endothelial barrier integrity. Tools for achieving reversible, spatiotemporally resolved modulation of intracellular & centerdot;NO, without pharmacological or genetic manipulation, are currently lacking. Here, we present a light-activated, nanoparticle (NP)-based strategy enabling bidirectional control of endogenous & centerdot;NO in endothelial cells. Composite NPs, based on poly(3-hexylthiophene), P3HT, and poly(3,4-ethylene-dioxythiophene):poly(styrenesulfonate), PEDOT:PSS polymers, are efficiently internalized in human (HUVEC) and murine (H5V) endothelial cells. In dark, NP uptake induces a ROS-dependent, intracellular & centerdot;NO increase (+50% and +100% in HUVEC and H5V, respectively, vs. controls), a metabolic shift toward glycolysis and upregulation of both endothelial nitric oxide synthase (eNOS, +50%) and induced nitric oxide synthase (iNOS, +40%). NP photostimulation reverses this response, decreasing & centerdot;NO below basal levels, up to -40% in HUVEC and H5V, via ROS-mediated scavenging and iNOS downregulation (-40%), partially restoring oxidative phosphorylation metabolism. Importantly, the photoexcitation protocol is compatible with perspective in vivo use, in terms of source type (LEDs) and power density (6 mW/cm2). Our approach represents an innovative strategy for bidirectional endothelial & centerdot;NO modulation, providing new opportunities in the emerging field of photo-redox medicine.