UNVEILING THE PATHOGENETIC MECHANISMS OF GOLD NANOPARTICLE TOXICITY: THE INTERPLAY OF SIZE, SURFACE CHEMISTRY, AND CELLULAR RESPONSE

INTRODUZIONE Gold nanoparticles (AuNPs) are widely investigated for biomedical applications; however, their potential to trigger adverse pathogenetic pathways remains a major safety concern. The molecular mechanisms driving AuNP-induced cellular stress and inflammation are strictly governed by their physical dimensions coupled with the surface chemical/electronic state. Nevertheless, the biophysical surface properties responsible for driving adverse pathogenetic and inflammatory responses remain to be fully elucidated. The CheMatSustain project, funded by the European Union’s Horizon Europe research and innovation program (Grant Agreement No. 101137990), investigates how variations in AuNP size and in the type of stabilizer, specifically sodium citrate and polyethylene glycol (PEG), dictate specific pathogenetic outcomes in vitro. METODI AuNPs of different sizes were functionalized with either sodium citrate or PEG. To highlight structure–activity relationships, surface chemical and electronic states were characterized by X-ray and Ultraviolet photoelectron spectroscopy (XPS/UPS), coupled with a novel artificial intelligence (AI)-driven data analysis model. Pathogenetic mechanisms were investigated in vitro by assessing cytotoxicity and TLR4-mediated inflammatory markers activation (IRAK1, miR-146a, and IL-6). RISULTATI Depending on surface/size/stabilizers, AI-powered XPS/UPS analysis revealed that AuNPs exhibited quantum size effects and different valence band profiles. Depending on AuNPs' pathogenetic response, cytotoxicity and modulation of inflammatory markers suggest their ability to interact differently with cellular metabolism and molecular pathways. CONCLUSIONI Our findings demonstrate that the pathogenetic response induced by AuNPs are dependent on the surface characteristics of the nanoparticle. The synergistic convergence between surface physics (AI-powered XPS/UPS) and molecular profiling may bridge the gap between materials science and translational medicine. Integrating XPS/UPS characterization with toxicological profiling provides insights into the molecular mechanisms of nanomaterial toxicity, offering a predictable framework for the design of safer, non-pathogenic nanotherapeutics.