Beyond luciferase-luciferin system: Modification, improved imaging and biomedical application

The bioluminescence signal generated by the luciferase-luciferin interaction, exploited for real-time and continuous monitoring of numerous biochemical processes in living cells and animals, is the foundation for in vivo bioluminescence imaging (BLI). However, many in vivo BLI application remains constrained due to the limited photon production and sensitivity in deep tissues. To obtain brighter bioluminescence images, various modified luciferase-luciferin emitting systems were developed by mutating suitable luciferase enzyme sites, replacing the substrate with its analogs, or inserting unnatural amino acids. In this review, we describe recent advances in modifying natural luciferase reporter systems to improve the sensitivity of in vivo BLI and extend the biomedical applications.