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 H2 O2 (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.

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