Microenvironment-Activatable Long-Wavelength NIR-II Visualization and Synergistic Treatment of Pulmonary Embolism

Pulmonary embolism (PE) is a life-threatening thrombotic condition, yet its precise diagnosis and effective treatment remain a major clinical challenge. In this study, we report the development of a microenvironment-activatable nanoplatform that enables hypoxia-triggered long-wavelength second near-infrared (NIR-II) fluorescence imaging for accurate thrombus visualization, combined with photothermal therapy (PTT) and controlled hydrogen sulfide (H₂S) release for synergistic therapeutic intervention. We first synthesize an <i>N</i>-oxide-based molecular probe that undergoes hypoxia-induced structural transition, thereby activating both NIR-II fluorescence and photothermal properties. This probe, together with a thermosensitive H₂S donor, is encapsulated into nanoparticles, which are further functionalized with bis-serotonin groups to achieve thrombus-specific targeting via the myeloperoxidase and hydrogen peroxide-mediated aggregation. In a PE mouse model, the nanoagent enables highly selective and sensitive visualization of thrombi via activatable NIR-II fluorescence imaging after intravenous injection, achieving a remarkable signal-to-noise ratio exceeding 120. The combined PTT and H₂S therapy significantly enhance thrombolytic efficacy compared to conventional treatment (e.g., urokinase). Importantly, the nanoagent exhibits excellent biocompatibility in vivo, with minimal risk of hemorrhagic complications. This high-performance hypoxia-responsive platform offers a promising strategy for the precise diagnosis and effective treatment of PE and other cardiovascular diseases.