A “Dual‐Source, Dual‐Activation” Strategy for an NIR‐II Window Theranostic Nanosystem Enabling Optimal Photothermal‐Ion Combination Therapy

Abstract The activatable imaging technique in the second near‐infrared window (NIR‐II) utilizes the stimulation of cancer‐associated biomarkers for specific imaging to guide precise NIR‐II photothermal therapy. However, most activatable nanoprobes with single‐source stimulation are insufficient in providing comprehensive information regarding the tumor, severely restricting the therapeutic optimization, especially in NIR‐II photothermal therapy (PTT)‐based combination therapy. Herein, a “dual‐source, dual‐activation” strategy‐based multifunctional nanosystem, PPAC, is reported as a promising tool for activatable NIR‐II fluorescence (FL)/ratiometric photoacoustic (PA) imaging‐guided “localization‐timing” photothermal‐ion therapy (PTIT). A fibroblast activation protein (FAP)‐responsive peptide to modify the surface of Pd nanosheets with excellent NIR‐II absorption ability can efficiently cross‐link BSA‐CQ4T to realize NIR‐II FL quenching, followed by the loading of Ag to construct the PPAC. Triggered by the specific cleavage with FAP on the perivascular cancer‐associated fibroblasts (first source), the PPAC can correspondingly release BSA‐CQ4T for rapid fluorescence recovery. The nanosystems are subsequently taken up by tumor cells, where the overexpressed H 2 O 2 (second source) promotes the oxidation of Ag shell to Ag + , and further leads the real‐time ratiometric PA signals (Ag‐PA660/Pd‐PA1050) that can monitor the Ag + ions‐related production efficiency and therapeutic performance. Intelligent integration of dual‐modality imaging information can comprehensively provide the right time‐point and site‐specificity for selective NIR‐II PTT.