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 N-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.