Tetris-like acceptor engineering: evolution of NIR-II aggregation-induced emission luminogens for one-for-all phototheranostics of orthotopic breast cancer

The pursuit of versatile second near-infrared (NIR-II, 1000–1700 nm) phototheranostic agents (PTAs) with one-for-all features for tumor diagnosis and therapy presents formidable challenges, primarily stemming from the intricate excited-state energy dissipation pathways inherent to organic fluorophores, notwithstanding their compelling clinical potential in precision oncology. Herein, we devised an innovative Tetris-inspired acceptor engineering to construct NIR-II emissive aggregation-induced emission (AIE) luminogens (FRx, x = 3–8). Through systematic elongation of the π-conjugated N-heteroacene (NHAs) scaffold from three to eight, we meticulously elucidated the structure-property relationship governing photophysical behaviors in both molecular and aggregate states, thereby achieving optimal energy partitioning for theranostic optimization. Notably, the length of the acceptor structure can finely modulate the absorption/emission behaviors in the single-molecular state. In the aggregated states, molecule FR8 with the longest NHAs structure was demonstrated to form Davydov split aggregates with two distinct absorption peaks at 722 and 773 nm, a shoulder at 612 nm, along with two intense emission peaks at 925 and 1000 nm due to V-shaped stacking fashion, endowing FR8 aggregates with boosted photophysical characteristics. The superiorities of FR8 nanoparticles enable exceptional performance in NIR-II fluorescence-photoacoustic-photothermal trimodal imaging guided photodynamic-photothermal synergistic therapy against mouse orthotopic breast cancer. Our present work provides a paradigm for preliminary tuning phototheranostic features via the manipulation of acceptor conjugation length and would inspire further development of versatile PTAs for clinical trials.