Nitric Oxide Conjugation Transforms NIR‐II AIEgens Into Potent Hypoxia‐Tolerant Type I Photosensitizers

ABSTRACT Near‐infrared (NIR)‐activated type I photosensitizers (PSs) with aggregation‐induced emission (AIE) properties are highly attractive for photodynamic therapy (PDT) of deep‐seated and inoperable tumors. However, most NIR‐activated AIEgens, especially donor–acceptor–donor (D‐A‐D) benzobisthiadiazole derivatives, are mainly used for bioimaging and photothermal therapy due to their intrinsically small S 1 →S 0 energy gaps (Δ E S1‐S0 ) severely limiting reactive oxygen species (ROS) generation. Here, we present a strategy to convert widely adopted D‐A‐D NIR‐activated AIEgens into NIR‐activated type I PSs by conjugating nitric oxide (NO) to the electron‐donating units. Upon NO conjugation, the resulting compounds NO‐T‐TQT and NO‐2TT‐ o C6B become efficient generators of NIR‐activated hydroxyl radical (•OH), exhibiting a 13.2‐fold and 5.4‐fold increase in superoxide (O 2 •− ) production compared with their parent molecules, respectively. In contrast, T‐TQT, 2TT‐ o C6B, and related analogues produce negligible ROS and no detectable •OH. Mechanistic studies reveal that NO conjugation narrows the singlet‐triplet energy gap, strengthens spin‐orbit coupling to enhance intersystem crossing, optimizes redox potentials to favor electron transfer, and lowering hydrogen atom affinity. NO‐2TT‐ o C6B nanoparticles achieved potent in vitro cytotoxicity and effective in vivo tumor ablation under NIR irradiation. This work establishes a general approach to transform conventional NIR‐activated D‐A‐D AIEgens into high‐performance type I PSs, significantly advancing their clinical potential in PDT.