Dual‐Locked Glutathione‐Activatable Nanoassemblies With Cascade Energy Transfer for Amplified Photodynamic Immunotherapy

Photodynamic immunotherapy is constrained by the immunosuppressive tumor microenvironment (TME) that scavenges reactive oxygen species (ROS) and limits immunogenic cell death. Lanthanide‐doped upconversion nanoparticles enable near‐infrared‐triggered singlet oxygen generation, yet their efficacy is hampered by intrinsically low upconversion luminescence efficiency and glutathione‐mediated ROS quenching. Here we report a dual‐locked glutathione (GSH)‐activatable nanoassembly (Cy‐UCMA) that integrates cascade energy transfer with self‐reinforcing oxidative stress. The system employs a nitroazo‐ether probe (Cy‐GSH) that remains optically silent until encountering two orthogonal triggers: endogenous GSH (biochemical key) and 808 nm light (physical key). GSH triggers nucleophilic aromatic substitution to generate a NIR‐absorbing antenna (Cy‐SG), which sensitizes Nd 3+ ‐doped UCNPs via non‐radiative energy transfer ( Φ = 45%), boosting upconversion luminescence by 2.7‐fold. Enhanced emission drives fluorescence resonance energy transfer ( Φ = 22%) to iron‐porphyrin units within PCN‐222(Fe), increasing 1 O 2 generation by 2.02‐fold. Concurrent Fe 3+ ‐mediated GSH depletion disrupts redox homeostasis, creating a positive feedback loop of oxidative stress. This chemo‐optically gated nanoplatform induces robust immunogenic cell death, promotes dendritic cell maturation, enhances cytotoxic T‐cell infiltration, and suppresses both primary tumors and pulmonary metastases. Our work establishes a bio‐orthogonal activation paradigm that bridges molecular switching with nanoscale energy transfer for precision cancer immunotherapy.