A membrane-to-nucleus targeting photosensitizer featuring aggregation-induced emission for dual-color imaging-guided antifungal therapy and biofilm disruption

The management of superficial fungal infections is a major global public health burden, driving the need for precise and resistance-free therapies. While photodynamic therapy (PDT) mediated by photosensitizers (PSs) offers a promising alternative, the lack of self-reporting capability in antifungal PSs hampers the accurate control of treatment and increases collateral risk from excessive reactive oxygen species (ROS). In this work, we designed and synthesized a series of aggregation-induced emission (AIE) PSs consisting of triphenylamine and 1H-indene-1,3(2H)-dione units, and found a versatile PS (named as ITTPM) that not only generates ROS efficiently but also simultaneously discriminates between live and dead fungi via a distinct fluorescence signal switch. In live fungi, ITTPM targets the cell membranes emitting red fluorescence. Upon fungal cell death, it relocates to the nuclei, staining them green. Mechanistic investigations via molecule imaging, lipid membrane mimicking experiment, DNA-responsive experiments and molecular docking revealed that ITTPM interacts with fungal membrane phospholipids via its aryl-substituted indanedione fragment and one pyridinium group in live fungi, versus binding to DNA bases via two cationic pyridinium fragments in dead cells. Furthermore, ITTPM shows potent photodynamic antifungal efficacy against planktonic fungi, effectively inhibits biofilm formation, and eradicates mature biofilms. In vivo studies on fungi-infected mouse wounds demonstrated that ITTPM achieved complete fungal eradication, facilitated wound healing and exhibited excellent biocompatibility. This study provides a promising candidate PS for precise clinical treatment of superficial fungal infections and novel insights into developing multifunctional antifungal PSs.