ABSTRACT Bioluminescence (BL) is a unique chemiluminescent process in living organisms that has inspired extensive applications in bioimaging and biosensing due to its high sensitivity, non‐invasiveness, and absence of background autofluorescence. Most luminescent organisms emit light through a set of luminescent systems. Some luminescent organisms possess an additional antenna protein that can receive energy from the former luminescent system. And the BL is emitted by the antenna protein. Inspired by these natural phenomena, bioluminescence resonance energy transfer (BRET) has been widely exploited to overcome the limitations of native BL, particularly the intensity and short‐wavelength emission that restrict deep‐tissue imaging. This review summarizes the fundamental mechanisms of ET in representative natural BL systems, combining insights from experimental and theoretical studies. We then conclude recent advances in engineering BRET systems by coupling luciferases with fluorescent proteins, organic dyes, and nanomaterials to achieve brighter and red‐shifted emissions, extending into the near‐infrared II (NIR‐II) region. Finally, we discuss current challenges and propose future directions for developing next‐generation BL probes with improved brightness, spectral tunability, and stability. We anticipate that these developments will provide powerful tools for real‐time imaging of biological processes with high resolution and penetration depth.
Pi et al. (2026) studied this question.