Mitochondria-targeting Type I AIE photosensitizer combined with H2S therapy: Uninterrupted hydroxyl radical generation for enhancing tumor therapy

Although Type I photosensitizers with aggregation-induced emission (AIE) characteristics have thrived as alternative tools for cancer photodynamic therapy (PDT) thanks to their efficient reactive oxygen species (ROS) generation and hypoxia resistance, accumulated reducing substances sinside the tumor and the short lifespan of ROS limit their therapeutic effects. How to continuously generate long-lasting ROS in tumors remains a thorny problem. Herein, we constructed an uninterrupted ROS generator by incorporating the H2S donor, (NH4)2S, and a Type I AIE photosensitizer, TDCAc, into an injectable agarose hydrogel, namely TSH. Mitochondria-targeting TDCAc exhibited excellent performance in multi-model Type I photodynamic/photothermal therapy under near-infrared laser irradiation. While (NH4)2S generates H2S gas in the acidic tumor microenvironment upon photothermal dissolution of TSH gel, which diffuses into cancer cells and effectively inhibits intracellular catalase activity. Thus, the intrinsic H2O2 consumption pathway is blocked to promote endogenous labile iron pool-mediated continuous hydroxyl radical (·OH) generation in tumors. In both in vitro and in vivo experiments, uninterrupted massive production of·OH in cancer cells after laser irradiation of TSH gels was demonstrated. Notably, H2S gas therapy is firstly combined with Type I AIE PDT, affording a novel synergistic strategy of continuous·OH generation for boosting tumor therapy.