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

ABSTRACT

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.