An AIE-active centrosymmetric small molecule for ultra-deep three-photon brain angiography in the NIR-III window
Three-photon microscopy (3PM) in the near-infrared-III (NIR-III) window (1600–1840 nm) enables high-resolution visualization of cerebral vasculature in vivo, but its imaging depth and quality are limited by the performance of fluorescent probes. Here, we report a probe optimization strategy transitioning from mirror symmetry to centrosymmetry, yielding a highly symmetric aggregation-induced emission (AIE) molecule, T4PQ. The centrosymmetric structure aligns donor-acceptor units, promoting uniform electron cloud delocalization and directional charge transfer, which enhances exciton formation and suppresses non-radiative decay, thereby increasing fluorescence quantum yield. This symmetry also boosts the three-photon absorption cross-section by enhancing electron delocalization and transition dipole moment, enabling stronger nonlinear optical responses under long-wavelength excitation. T4PQ nanoparticles (T4PQ NPs) exhibit an enhanced three-photon absorption cross-section, high fluorescence quantum yield, and excellent photostability. In murine models, T4PQ NPs achieved three-dimensional cerebrovascular imaging at a depth of 1785 μm and real-time hemodynamic observation in microvessels at 1006 μm depth, with good biocompatibility. These results validate the advantage of centrosymmetric molecular design for deep-brain imaging probes, offering a high-performance tool for neurovascular research.