Bioactive Light-Responsive Au Nanohybrids for Reactive Oxygen Species-Driven Macrophage Reprogramming

Optical modulation of immune responses via nanomaterials has emerged as a promising approach in cancer immunotherapy, but challenges in achieving precise activation with minimal phototoxicity persist. In this study, we developed a galactose-functionalized Au-S (2ATP)/polyaniline (PANI)-based glycopolymer nanoparticle (Au/2ATP@PGlyco NP) to enable multivalent galactose-based biostimulation of M2-like macrophages and hot electron/hole-elicited reactive oxygen species (ROS) generation for synergistic macrophage reprogramming. The 2ATP@PANI-based shell not only facilitated light-driven charge transfer to enhance ¹O₂ generation but also provided Raman-active properties that enabled single-cell visualization of phenotypic transitions toward the M1 phenotype through the NF-κB and STAT-1-mediated pro-inflammatory signaling. Such light-driven reprogrammed M1-like macrophages with Au/2ATP@PGlyco NP effectively induced apoptosis in MB49 bladder cancer cells through phagocytosis and the release of TNF-α and IL-12, resulting in a potent antitumor effect. This research highlights a new nanobiophotonics platform that holds potential for advancements in macrophage modulation within cancer immunotherapy.