Developing Dual-State Emission Berberine Derivatives as Theranostic Agents by Reducing Nonradiative Transition Pathways

Berberine, an antibacterial natural product, shows promise as a theranostic agent. However, berberine exhibits moderate antibacterial efficacy and limited water solubility, restricting its clinical application. In this study, we discovered that a berberine derivative B-12 exhibits dual-state emission (DSE) characteristics, and its photodynamic antibacterial activity is significantly higher than that of berberine and methylene blue. The mechanistic studies suggested that substitution with a single methoxy group at the C-3 position reduces the intramolecular electron transfer and increases the energy gap between singlet and triplet excited states, which reduces nonradiative transition pathways and improves the fluorescence quantum yield. The C-3 methoxy group also contributes to higher ROS production due to the longer lifetime of the excited state. Through bioimaging, B-12 was able to discriminate between Gram-positive and Gram-negative bacteria. Notably, this study offers valuable insights for designing photodynamic and DSE-active berberine derivatives, highlighting the potential of these derivatives as theranostic agents.