Amino‐Acid‐Encoded Supramolecular Nanostructures for Persistent Bioluminescence Imaging of Tumor

Bioluminescence imaging (BLI) is a powerful technique for noninvasive monitoring of biological processes and cell transplantation. Nonetheless, the application of D‐luciferin, which is widely employed as a bioluminescent probe, is restricted in long‐term in vivo tracking due to its short half‐life. This study presents a novel approach using amino acid‐encoded building blocks to accumulate and preserve luciferin within tumor cells, through a supramolecular self‐assembly strategy. The building block platform called Cys(SEt)‐X‐CBT (CXCBT, with X representing any amino acid) utilizes a covalent‐noncovalent hybrid self‐assembly mechanism to generate diverse luciferin‐containing nanostructures in tumor cells after glutathione reduction. These nanostructures exhibit efficient tumor‐targeted delivery as well as sequence‐dependent well‐designed morphologies and prolonged bioluminescence performance. Among the selected amino acids (X = Glu, Lys, Leu, Phe), Cys(SEt)‐Lys‐CBT (CKCBT) exhibits the superior long‐lasting bioluminescence signal (up to 72 h) and good biocompatibility. This study demonstrates the potential of amino‐acid‐encoded supramolecular self‐assembly as a convenient and effective method for developing BLI probes for long‐term biological tracking and disease imaging. Amino‐acid‐encoded supramolecular nanostructures for sustained bioluminescent tumor imaging: The building block platform Cys(SEt)‐X‐CBT is used here as a bioluminescent probe that utilized a covalent‐noncovalent hybrid self‐assembly mechanism to generate diverse luciferin‐containing nanostructures in tumor cells after glutathione reduction. Subsequently, the nanostructures are cleaved by protease to generate luciferase substrates for prolonged bioluminescence imaging in luciferase‐expressing tumors.