Chemiluminescence Resonance Energy Transfer for Targeted Photoactivation of Ion Channels in Living Cells

Abstract The regulation of oxidative stress in living cells is essential for maintaining cellular processes and signal transduction. However, developing straightforward strategies to activate oxidative stress‐sensitive membrane channels in situ poses significant challenges. In this study, we present a chemiluminescence resonance energy transfer (CRET) system based on a conjugated oligomer, oligo( p ‐phenylenevinylene)‐imidazolium (OPV−Im), designed for the activation of transient receptor potential melastatin 2 (TRPM2) calcium channels in situ by superoxide anion (O 2 ⋅ − ) without requiring external light sources. The OPV−Im oligomer targeted the cell membrane efficiently, leading to the activation of TRPM2 channels in situ by the CRET process and subsequent intracellular calcium overload. This cascade resulted in mitochondrial damage and inhibition of autophagy, ultimately inducing cell apoptosis. Additionally, this strategy could be applied for the selective killing of tumor cells that overexpress TRPM2 ion channels and for inhibiting the growth of three‐dimensional (3D) tumor spheroids. Our system offers a novel approach for regulating ion channel activity and oxidative stress in living cells compared to optogenetics and photodynamic therapy.