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

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 S₁→S₀ energy gaps (ΔE_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-oC6B become efficient generators of NIR-activated hydroxyl radical (•OH), exhibiting a 13.2-fold and 5.4-fold increase in superoxide (O₂ ^•-) production compared with their parent molecules, respectively. In contrast, T-TQT, 2TT-oC6B, 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-oC6B 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.