Chemically Initiated Single-Module Afterglow Imaging via Lesion-Microenvironment-Activated Cyanine–Fe Coordination

Abstract Afterglow luminescence imaging offers high sensitivity, deep-tissue readability, and persistent emission for image-guided surgery, but most current probes still require external energy activation, limiting autonomous lesion reporting and increasing the risk of off-target tissue exposure. Here, we report a single-module afterglow platform without external physical activation based on Cy-His-Fe nanoparticles (NPs) for disease-microenvironment-activated imaging and surgical guidance. In this system, tumor-associated hydrogen peroxide (H2O2) and weak acidity activate the peroxidase (POD)-like activity of Fe centers, generating hydroxyl radical (OH•) that oxidizes the Cy-His scaffold and triggers sustained NIR afterglow emission without exogenous physical preactivation. The resulting cRGD/Cy-His-Fe NPs achieved a 400-fold higher signal-to-background ratio and enabled afterglow detection through tissue barriers up to 2.0 cm. In vivo, the tumor afterglow signal peaked at approximately 6 h postinjection and remained detectable for up to 9 h, providing a prolonged imaging window for subcutaneous tumor localization, orthotopic lung tumor imaging, and afterglow-guided identification of residual lesions for secondary resection. Free Cy-His was further activated in situ by the Fe-rich and oxidative microenvironment of FeCl3-induced arterial thrombosis, enabling thrombus afterglow visualization. This work establishes a self-activating cyanine–Fe coordination platform for disease-microenvironment-driven afterglow imaging and precision surgical navigation.