Engineering Gold Nanoconstruct Architecture Dictates Absorption Efficiency and Photoacoustic Imaging Performance

Abstract

Photoacoustic (PA) imaging combines the high contrast of optical modalities with the deep-tissue penetration and high-spatial resolution of ultrasound, making it an attractive technique for biomedical imaging. Gold nanoconstructs are among the most widely investigated PA imaging probes due to their strong, tunable optical extinction, and excellent photostability. However, despite extensive development of gold nanomaterials, the mechanisms through which nanoconstruct architecture influences PA performance remain incompletely understood, limiting the rational design of next-generation probes. Here, we investigate how engineering gold nanoconstruct architecture dictates PA imaging performance across the near-infrared window. Six gold nanoconstructs representing the three most (pre)clinically relevant architectural classes, namely nanostars, nanorods, and nanoshells, were developed and engineered to exhibit localized surface plasmon resonances centered at either 800 or 980 nm. Using a standardized framework comprising physicochemical characterization, biological studies, in vitro and ex vivo PA imaging, and quantitative PA point-source modeling, we established relationships between nanoconstruct architecture, absorption efficiency, and PA performance. All formulations generated concentration-dependent PA signals in vitro and detectable contrast in biological tissue ex vivo, while maintaining excellent photostability under continuous irradiation with a pulsed laser. Marked architecture-dependent differences were observed, with nanoshells and nanostars consistently outperforming nanorods (up to 5-fold), particularly those resonant at longer wavelengths, attributed to their higher absorption cross sections per nanoparticle volume, as determined by PA modeling. Beyond PA performance, nanostars and nanoshells also exhibited superior colloidal stability in biological media, whereas all formulations displayed minimal cytotoxicity. Among the investigated architectures, gold nanostars resonating at 980 nm emerged as a particularly promising candidate, combining strong PA signal generation with a size profile more favorable for in vivo applications. Collectively, these findings demonstrate that engineering gold nanoconstruct architecture manipulates absorption efficiency and consequently PA imaging performance, providing a framework for rational engineering of next-generation PA imaging probes.