From Molecule to Aggregate: Designing AIE Nanocrystals for Low‐Power Backward Third‐Harmonic Generation Angiography

Organic materials featuring third harmonic generation (THG) hold great promise for deep-tissue bioimaging due to their good biocompatibility and second near-infrared excitation. However, minimizing photodamage from the incident light necessitates significant improvements in the third-order nonlinear susceptibility. Herein, an organic luminogen called OTBP is developed as a backward THG (BTHG) contrast agent for second near-infrared (NIR-II) angiography. OTBP's intense absorption at 433 nm resonantly enhances its BTHG efficiency when excited by a 1300 nm femtosecond laser. In the aggregate state, the robust intermolecular interactions among OTBP molecules realize excellent crystallinity and the facile preparation of nanocrystals (NCs) with a high refractive index of 1.78. By leveraging Mie scattering theory, the best size of OTBP NCs for BTHG collection is attained. These integrated properties result in a high BTHG efficiency of OTBP NCs. Encapsulating the NCs with F-127 enables ultralow-power but high-contrast 3D vasculature imaging with negligible photodamage and background interference. Further elevating the laser power to 60 mW enables the visualization of microvessels at 500 µm with a high SNR of 143. This study offers insights into material design strategies toward efficient organic BTHG contrast agents and paves the way for the materials-oriented non-linear optics.