Spectroscopic insights and theranostic application of a CD44-targeted, GSH/H2S-dual-responsive AIE micellar nanoplatform for targeted tumor imaging and photodynamic therapy.

Stimuli-responsive theranostic nanoplatforms have garnered significant attention for their potential to boost diagnostic precision and photodynamic therapy (PDT) efficacy in cancer treatment. Here, we engineered a tumor microenvironment (TME) dual-responsive aggregation-induced emission (AIE) micellar system (HA-SS-TPEDCH-Th) to achieve receptor-guided specific bioimaging and localized photodynamic ablation. By harnessing hyaluronic acid (HA) as an active targeting shell, the micelles selectively internalized into CD44-overexpressing hepatic tumor cells, where the simultaneous presence of elevated glutathione (GSH) and hydrogen sulfide (H2S) unlocked a strict "AND" logic gate, facilitating complete micelle dissociation and instant AIE fluorescence turn-on. The stimulus-released payload thoroughly eliminated false-positive background signals in healthy cells and induced a robust, highly localized reactive oxygen species (ROS) burst under specific laser irradiation, severely suppressing tumor cell viability. Of note, in dense three-dimensional (3D) multicellular tumor spheroids, HA-SS-TPEDCH-Th demonstrated remarkable deep tissue penetration and elicited profound photodynamic damage, abruptly initiating a mitochondrial-mediated intrinsic apoptosis cascade that led to the irreversible morphological disintegration of the robust spheroids. Together, our study highlights the translational promise of actively targeted, dual-locked AIE micelles as a highly specific, zero-premature-release theranostic platform for advanced solid tumor eradication.