Charge modulation in D–A–D molecules: an acid-responsive NIR-II nanoplatform for imaging and photothermal therapy

Small-molecule near-infrared (NIR) dyes have shown great promise in bioimaging and theranostics of diseases. Among them, D-A-D-structured molecules stand out because of their excellent photostability, second near-infrared window (NIR-II, 1000-2000 nm) emission, and large Stokes shifts, offering significant imaging advantages and application potential. However, compared to conventional BODIPY and cyanine-based dyes, D-A-D molecules are generally uncharged and exhibit poor solubility, which limit their further application in biological systems. To date, systematic studies on the photophysical properties of charged D-A-D molecules have remained scarce. Considering the importance of structural modulation, a detailed investigation of their optical properties is of great significance for rational design of practical and high-performance dyes. In this study, two groups of D-A-D-type small-molecule dyes were rationally designed and synthesized based on a donor-acceptor engineering strategy. The influence of charge incorporation on their photophysical properties was systematically evaluated. Among them, SMIC-10004 exhibited excellent optical stability, good polarity, and favorable NIR-II emission characteristics. Based on this, an acid-responsive nanoprobe, SMIC-10004 NPs, was constructed using mPEG-Hyd-DSPE to enhance accumulation in the tumor microenvironment. <i>In vivo</i> experiments demonstrated that SMIC-10004 NPs enabled high-resolution and long-term NIR-II imaging, and the nanoparticles significantly inhibited tumor growth under laser irradiation, showing superior photothermal therapeutic efficacy with good biocompatibility. Overall, this study not only provides valuable guidance for the rational design of charged D-A-D dyes, but also presents a promising platform for NIR-II-based theranostic applications.