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 MnO₂ 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 MnO₂ shell to Mn²⁺ realizes GSH‐depletion, which is a distinctive approach for elevating intracellular ·OH. Meanwhile, the generated Mn²⁺ can implement T₁‐weighted magnetic resonance imaging (MRI) in specific tumor sites, and mediate the conversion of intracellular H₂O₂ 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.