A super-inert near-infrared fluorescent rotaxane dye for surgical navigation

Near-infrared (NIR) fluorescent emitters in the NIR-I (800–1,000 nm) and NIR-II (1,000–3,000 nm) windows are increasingly deployed in preclinical and clinical settings. Aqueous solubility and biocompatibility, which are crucial for their biological use, are commonly achieved by introducing multiple charged groups onto fluorophores. Yet, this method introduces undesired non-specific binding and high-cost synthesis. Here we report a near-neutral cyanine/α-cyclodextrin rotaxane dye with excellent aqueous solubility (~29 mg ml−1), negligible binding and retention by serum proteins, organs and tissues. The dye also undergoes complete renal excretion within hours after administration and exhibits superior stability. These properties arise from the encapsulation of the molecular backbone by α-cyclodextrin threading. The super-inert dye, named SID-788, affords high-performance ureter imaging in mice and pigs using NIR-II wide-field and clinically approved NIR-I laparoscopes and robotic surgical systems. Threading dye molecules through cyclodextrin provides a versatile strategy for engineering fluorescent probes with excellent biocompatibility, brightness and stability. This design enables safe dosage up to 500 times the standard imaging dose (0.5 mg kg−1), paving the way for their potential clinical translation. A threaded α-cyclodextrin rotaxane near-infrared (NIR) dye offers superior photostability, high solubility, negligible non-specific binding and complete renal clearance, enabling ureter imaging in mice and pigs via NIR-II imaging and clinical NIR-I laparoscopes.