A Targeted, Tandem-Activated Artificial Urinary Biomarker Sensor for Early Detection and Therapeutic Intervention of Thoracic Aortic Aneurysm and Dissection.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular disorder; current clinical imaging approaches primarily detect structural abnormalities at late stages and fail to enable early diagnosis or dynamic therapeutic monitoring. Here, we develop a targeted, tandem-activated artificial urinary biomarker sensor (TADEI) for real-time optical imaging and urinalysis of early biomarkers associated with TAAD. After identifying biomarkers from patient tissue samples, TADEI was designed with three key components conjugated to a near-infrared fluorophore: a VCAM-1-targeting moiety (overexpressed on inflamed endothelial cells), tandem-responsive substrates for caspase-1 (an inflammation mediator) and legumain (a protease relevant to vascular remodeling), and a renal-clearance-enabling moiety. TADEI specifically targets TAAD lesions and activates its fluorescence upon reaction with these early biomarkers after systemic administration. Meanwhile, TADEI is excreted into urine via renal clearance (≈76%), converting TAAD biomarker levels into urinary signals for optical urinalysis. In a mouse model, a TADEI-based urine test detected TAAD at least 12 days earlier than ultrasound imaging and 16 days earlier than plasma D-dimer assays. The correlation between the urinary signal of activated TADEI and disease severity guided intervention that effectively inhibited TAAD progression, achieving 100% survival compared with 73% for ultrasound-guided therapy and 40% without treatment.