Triple‐Jump Photodynamic Theranostics: MnO2 Combined Upconversion Nanoplatforms Involving a Type‐I Photosensitizer with Aggregation‐Induced Emission Characteristics for Potent Cancer Treatment

Abstract The development of multifunctional nanoplatforms has been recognized as a promising strategy for potent photodynamic theranostics. Aggregation‐induced emission (AIE) photosensitizers undergoing Type‐I reactive oxygen species (ROS) generation pathway appear as potential candidates due to their capability of hypoxia‐tolerance, efficient ROS production, and fluorescence imaging navigation. To further improve their performance, a facile and universal method of constructing a type of glutathione (GSH)‐depleting and near‐infrared (NIR)‐regulated nanoplatform for dual‐modal imaging‐guided photodynamic therapy (PDT) is presented. The nanoplatforms are obtained through the coprecipitation process involving upconversion nanoparticles (UCNPs) and AIE‐active photosensitizers, followed by in situ generation of MnO 2 as the outer shell. The introduction of UCNPs actualizes the NIR‐activation of AIE‐active photosensitizers to produce ·OH as a Type‐I ROS. Intracellular upregulated GSH‐responsive decomposition of the MnO 2 shell to Mn 2+ realizes GSH‐depletion, which is a distinctive approach for elevating intracellular ·OH. Meanwhile, the generated Mn 2+ can implement T 1 ‐weighted magnetic resonance imaging (MRI) in specific tumor sites, and mediate the conversion of intracellular H 2 O 2 to ·OH. These outputs reveal a triple‐jump ·OH production, and this approach brings about distinguished performance in FLI‐MRI‐guided PDT with high‐efficacy, which presents great potential for future clinical translations.