As AIE Meets J‐Aggregation: Subtle Molecular Regulation to Modulate Intermolecular Packing of Aggregates for NIR‐IIa In Vivo Bioimaging

Abstract The development of high‐performance organic fluorescent probes for near‐infrared‐IIa (NIR‐IIa) intravital imaging is highly desirable yet remains a formidable challenge due to the paucity of reliable molecular design strategies. Addressing this limitation, an innovative approach leveraging aggregate science is presented to engineer a robust NIR‐IIa probe through synergistic integration of aggregation‐induced emission (AIE) and J‐aggregation. By fine‐tuning molecular conformation and donor‐acceptor interaction strength to systematically modulate intermolecular packing patterns in the aggregated state, an optimized organic compound named DTE‐BD is successfully screened out, which concurrently exhibits AIE property and J‐aggregation behavior when formulated into nanoparticles (NPs). This dual functionality effectively overcomes the limitations of aggregation‐caused quenching and energy gap law inherent in traditional molecular engineering approaches, endowing DTE‐BD NPs with superior NIR‐IIa emission peaking at 1262 nm. Coupled with optimal hydrodynamic size, excellent photostability, and good biocompatibility, DTE‐BD NPs enabled high‐resolution intravital angiography and demonstrated diagnostic potential for bone‐related pathologies. Surface functionalization with azide groups further conferred specific bone‐targeting capability, with proteomic analysis of the nanoparticle protein corona pioneeringly providing corresponding mechanistic elucidation. This work not only introduces an outstanding NIR‐IIa fluorescent probe but also establishes a novel design paradigm for developing high‐performance organic emitters through strategic manipulation of aggregation phenomena.