Oral ER-targeting near-infrared nanoprobes enable real-time intraoperative thoracic duct mapping in swine

The thoracic duct (TD), the largest lymphatic vessel in the human body, plays a critical role in returning lymph to the circulatory system. However, its dynamic, distensible nature and concealed anatomical location make intraoperative visualization critically challenging and increase the risk of injury. Real-time, high-resolution assessment of TD leaks remains an urgent clinical need. Here, we present a breakthrough molecular engineering strategy that leverages an intestinally lipophilic fluorescent formulation for dynamic in vivo TD imaging. Our rationally designed cyanine derivative IR790+, known for its rapid membrane permeability and endoplasmic reticulum (ER) targeting localization, demonstrates unprecedented chylomicron affinity, which subsequently transports the dye through the lymphatic system to the TD. Notably, dynamic, high-contrast intraoperative TD imaging is achieved from rat models to swine models. Administered orally as near-infrared (NIR) fluorescent contrast agent, this ultra-stable IR790+@oil formulation, engineered via flash nanoprecipitation, surpasses conventional counterparts by enabling non-invasive, real-time identification of TD. Intriguingly, this first-reported ER-targeting NIR formulation, delivered orally, represents a paradigm shift in fluorescence-guided surgery, significantly improving intraoperative accuracy.