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

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 H₂ O₂ 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.