Ingestible Artificial Urinary Biomarker Probes for Urine Test of Gastrointestinal Cancer

Although colorectal cancer diagnosed at an early stage shows high curability, methods simultaneously possessing point‐of‐care testing ability and high sensitivity are limited. Here, an orally deliverable biomarker‐activatable probe (termed as HATS) for early detection of orthotopic tumors via remote urinalysis is presented. To enable its oral delivery to the colon, HATS is designed to have remarkable resistance to acidity and digestive enzymes in the stomach and small intestine and negligible intestinal absorption. Upon reaction with a cancer biomarker in the colon segment, HATS releases a small fragment of tetrazine that can transverse the intestinal barrier, enter blood circulation, and ultimately undergo renal clearance to urine. Subsequently, the urinary tetrazine fragment is detected by bioorthogonal reaction with trans‐cyclooctene‐caged resorufin (TCO‐Reso) to afford a rapid and specific fluorescence enhancement of TCO‐Reso. Such signal readout is correlated with the urinary tetrazine concentration and thus measures the level of cancer biomarkers in the colon. HATS‐based optical urinalysis detects orthotopic colon tumors two weeks earlier than clinical serological tests and can be developed to a point‐of‐care paper test. Thereby, HATS‐based urinalysis provides a non‐invasive and sensitive approach to cancer screening at low‐resource settings. An ingestible artificial urinary biomarker probe can specifically react with cancer biomarkers in colon tumors and subsequently release renal‐clearable small tetrazine fragments, allowing for fluorescence turn‐on urine detection via bioorthogonal reaction with a trans‐cyclooctene‐caged fluorophore.