n-Hexyl side chain engineering: Crafting NIR-II AIEgens with balanced fluorescence-photothermal performance for precision tumor ablation

Photothermal therapy (PTT) has gained significant attention as a promising cancer treatment due to its low systemic toxicity, minimal invasiveness, and other advantages. Aggregation-induced emission luminogens (AIEgens) with second near-infrared (NIR-II) fluorescence have emerged as ideal photothermal agents (PTAs), offering key benefits such as high biosafety, excellent biocompatibility, and precise tumor theranostics. Nevertheless, achieving an optimal balance between radiation-mediated NIR-II fluorescence imaging and non-radiation NIR-PTT poses a considerable challenge in designing efficient NIR-II AIEgens. In this work, we employed side chain engineering by strategically grafting n-hexyl onto the π-bridge of a conjugated D-π-A-π-D structure, leading to the development of four new AIEgens (BQ1∼BQ4). These compounds feature 6,7-diphenyl- [1,2,5] thiadiazolo [3,4-g] quinoxaline as the acceptor, thiophene as the π-bridge, and phenothiazine as the donor. This molecular design enables precise regulation of backbone distortion, effectively balancing fluorescence emission and photothermal conversion. Among them, BQ1, BQ3, and BQ4 exhibited strong fluorescence, longer emission wavelengths, and superior photothermal conversion efficiencies (PCEs) (59.2 %, 57.8 %, 52 % respectively), whereas BQ2, with greater molecular distortion, showed a lower PCE of 33.4 %. Notably, BQ1 nanoparticles demonstrated outstanding photothermal conversion, prolonged tumor retention, strong resistance to photobleaching in vitro and in vivo, and NIR-II imaging capability at 1055 nm. This study introduces a novel strategy for optimizing NIR-II/AIE PTAs through precise conformational control via strategic n-hexyl positioning, which remains unreported to date.