Bacterial-mediated FRET between AIE and ACQ photosensitizers for enhanced antimicrobial photodynamic therapy

Antimicrobial photodynamic therapy (aPDT) effectively treats multidrug-resistant bacterial infections by utilizing photosensitizers to generate cytotoxic reactive oxygen species. Exploiting fluorescence resonance energy transfer (FRET) effect shows great potential for enhancing the efficacy of aPDT. Typically, this method involves encapsulating fluorescent molecules, including photosensitizers, into nanomaterials or coadsorbing them onto materials. Here, we develop a strategy that directly utilizes bacteria as carriers to bring two types of photosensitizers together to induce the FRET. We designed an aggregation-induced emission (AIE) photosensitizer (CPVBP3) and an aggregation-caused quenching (ACQ) photosensitizer (TPP3), both featuring the same bacterial membrane-targeting group to direct them to bacteria. Under white light exposure (12 J/cm2), the bactericidal effect of the combination of CPVBP3 and TPP3 at 5 µM each on Escherichia coli (4.7 log10) was much stronger than their individual use at 5 or 10 µM, highlighting synergistic antibacterial action. In Escherichia coli, TPP3 absorbed the fluorescence of CPVBP3, reducing its lifetime from 0.98 ns to 0.74 ns, confirming the occurrence of FRET. This combination also demonstrated a significantly stronger synergistic aPDT effect on Acinetobacter baumannii. Moreover, CPVBP3 synergized with methylene blue against Escherichia coli, indicating the universality of this strategy. Additionally, the efficacy and biosafety of this therapeutic approach were validated in a mouse wound model infected with Escherichia coli. In summary, this FRET strategy overcomes the limitations associated with the need for pre-binding photosensitizers with materials and the challenge of these mixtures penetrating bacteria (for greater damage), ultimately opening new avenues for further enhancing the efficacy of aPDT.