An Engineered Heavy-Atom-Free AIE-Active Type-I Sonosensitizer for NIR-II Imaging-Guided Sono-Immunotherapy of Hypoxic Tumors

Abstract The low oxygen dependence of the type-I sonosensitizers renders them promising agents for the treatment of hypoxic solid tumors. However, the rational design of heavy-atom-free type-I sonosensitizers with NIR-II emission remains challenging. Herein, a series of NIR-II heavy-atom-free sonosensitizers were synthesized. Among them, RBT-TPE02 exhibited pronounced aggregation-induced emission (AIE) characteristics, good NIR-II fluorescence, and efficient type-I reactive oxygen species generation under ultrasound irradiation. After nanoformulation, RBT-TPE02 NPs demonstrated notable type-I sonodynamic therapy (SDT) activity, which enabled efficient inhibition of tumor cells under hypoxic conditions and induced pyroptosis-associated immunogenic cell death upon ultrasound irradiation. In vivo experiments further confirmed that RBT-TPE02 NPs mediated efficient NIR-II imaging-guided SDT, resulting in effective tumor suppression and the activation of anti-tumor immune responses. This work presents a heavy-atom-free AIEgen engineering strategy that integrates NIR-II fluorescence, oxygen-independent type-I sonodynamic action, and pyroptosis-mediated immune activation in a single molecular platform for imaging-guided tumor therapy under hypoxia.