Regioisomeric Steric Engineering of Dibenzofulvene Photosensitizers for Efficient Type‐I Antibacterial Photodynamic Therapy

ABSTRACT

Biofilm‐associated infections represent a major clinical challenge owing to intrinsic hypoxia, restricted drug penetration and antimicrobial resistance. Among non‐antibiotic strategies, antimicrobial photodynamic therapy (a‐PDT) is particularly attractive owing to its spatiotemporal controllability, low systemic toxicity and multi‐target oxidative damage. However, most organic photosensitizers predominantly operate through oxygen‐dependent Type‐II pathways, rendering PDT severely compromised in hypoxic biofilm microenvironments. Although Type‐I PDT offers an oxygen‐insensitive alternative, its rational development is fundamentally restricted by the energy gap law. Herein, a steric‐control strategy is developed to regulate the triplet excited‐state alignment of dibenzofulvene‐based photosensitizers and enable a predominant Type‐I radical pathway. Through pyridinium, quinolinium incorporation and regioisomeric engineering, three dibenzofulvene‐based photosensitizers (FEMP, FEOMQ, and FEMQ) were constructed. Para‐quinolinium substituted FEMQ exhibits the narrowest Δ E _S1‐T2 and dominant Type‐I ROS generation. Consequently, FEMQ achieves rapid eradication of methicillin‐resistant Staphylococcus aureus (MRSA) at ultralow concentrations, efficient biofilm disruption, and significant therapeutic efficacy in a biofilm‐associated implanted catheter model. Overall, this work establishes dibenzofulvene‐based, sterically regulated photosensitizers as a rational platform for efficient Type‐I photodynamic antibacterial therapy and offers a promising non‐antibiotic strategy for persistent biofilm‐associated infections.