Small-Molecule Phototheranostics: A Decade of Molecular Design, Advances, and Future Perspectives

Abstract Phototheranostics is a rapidly advancing field that integrates light-based diagnostic and therapeutic interventions to provide spatiotemporally controlled outcomes. Consequently, it has emerged as a significant area of precision oncology over the past decade. Small-molecules offer distinct advantages, including high purity with reproducibility, well-defined chemical structures, and predictable pharmacokinetics, making them attractive candidates for clinical translation. In this review, we focus on the advancements in structurally defined, nonencapsulated small-molecules where the same molecular platform provides both diagnostic and therapeutic functionality. We first briefly describe the primary deep-tissue diagnostic techniques (near-infrared imaging and photoacoustic imaging), followed by therapeutic modalities (photodynamic therapy and photothermal therapy) that can be integrated and implemented to advance modern phototheranostics. Accordingly, we discuss several classes of small-molecule agents, ranging from platforms exhibiting aggregation-caused quenching to those exploiting aggregation-induced emission, as well as smart activatable probes that respond to tumor-associated biomarkers, including hypoxia and reactive oxygen species, through precise switching mechanisms. We further summarize the recent advances in molecular engineering strategies for extending the blood circulation of small-molecule phototheranostic agents, addressing one of the current key limitations of agents for in vivo translation. In addition, we have introduced dark quenchers as an emerging class of molecular systems and their potential applications in the field of phototheranostics. Finally, we present an in-depth discussion of persistent bottlenecks and provide future perspectives on emerging opportunities for next-generation clinical phototheranostics.