Multi‐Photonic Synergy: A Light‐Driven MOF‐Like Organometal–Phenolic Network Nanocage for Self‐Enhanced Fluorescence‐Guided Photothermal Therapy and Glutathione Depletion

ABSTRACT Integrated nanotheranostics face two obstacles: photolability of therapeutic agents and the antioxidative tumor microenvironment (TME) with elevated glutathione (GSH). This study introduces a light‐driven multi‐synergistic strategy to overcome these challenges. A dynamic, MOF (metal–organic framework)‐like ferrocene‐hyaluronic acid–tannic acid (FH‐TA) network is first constructed via natural light‐driven assembly. This network exhibits reversible disassembly selectively responsive to high tumor GSH (≥1 mM) and subsequent photo‐reassembly, enabling sustained catalytic GSH depletion. Subsequently, an FHT@ICG nanocage is engineered from this network. The intracage molecular confinement effect stabilizes indocyanine green (ICG), elevating its photothermal conversion efficiency (PCE) to ∼57.7% and enabling tumor‐specific off‐on fluorescence switching, thereby facilitating precise imaging‐guided photothermal therapy as the second synergy. Crucially, under 808 nm laser irradiation, excited ICG acts as a photosensitizer to drive ferrocene (Fc) oxidation via a photoinduced electron transfer (PET) process, thereby accelerating network reassembly and intensifying GSH depletion independent of endogenous H 2 O 2 . This establishes the third synergy: a self‐reinforcing therapeutic cycle integrating photocatalytic GSH depletion with photothermal ablation. Both in vitro and in vivo validations, including unilateral and bilateral tumor models, demonstrate effective tumor targeting, significant growth inhibition, and good biocompatibility without inducing significant toxicity. This work presents a novel technical pathway for developing intelligent theranostic platforms.