Finishing Touch via Metal Coordination: A Photoactivatable Organic Semiconducting Prodrug for Triply Synergistic Amplified Cancer Phototheranostics

ABSTRACT Photothermal therapy (PTT), photodynamic therapy (PDT), and NIR‑II fluorescence imaging are each compromised by tumor hypoxia, thermotolerance, and insufficient contrast, respectively, limiting the efficacy of integrated phototheranostics. To address these challenges, we developed a multi‑amplification theranostic nanoplatform (ReCO‐TPP NPs) that initially exhibits weak NIR‐II fluorescence, type I PDT, and PTT, yet undergoes substantial self‐amplification upon light irradiation. A rhenium(I) carbonyl complex was covalently conjugated to a D‐π‐A‐π‐D fluorophore (DTP), and the heavy‐metal center partially quenches the NIR‐II emission and suppresses type I ROS generation. Upon tumor accumulation and 808 nm laser irradiation, the limited initial ROS cleave the rhenium‐carbonyl bond, releasing CO and regenerating the free DTP fluorophore. This activation dramatically amplifies NIR‐II brightness and type I photodynamic activity, while maintaining excellent photothermal performance. The liberated CO suppresses heat shock protein 70, dissipates mitochondrial membrane potential, and inhibits ATP synthesis, thereby sensitizing tumor cells to PTT and establishing a self‐reinforcing ROS‐CO‐ROS cycle. Mitochondrial targeting via triphenylphosphonium further intensifies cellular damage. In 4T1 tumor‐bearing mice, ReCO‐TPP NPs enable deep‐tissue NIR‐II imaging with post‐irradiation brightness enhancement and produce potent synergistic antitumor efficacy. This molecularly engineered “weak‐to‐strong” theranostic strategy offers a promising paradigm for precisely amplified cancer phototheranostics.