PEGylated Hemicyanine-Based Dual-Mode Phototherapy Platform with Robust Antibacterial and Antibiofilm Activity against High Priority Pathogens

Antibiotic resistance, particularly in biofilm-associated infections, represents a major global health challenge. The increasing rate of multidrug-resistant pathogens, coupled with the slowdown in antibiotic discovery, underscores the urgent need for antibiotic-free therapeutic strategies. In this context, multimodal phototherapeutic agents that combine photodynamic therapy (PDT) and photothermal therapy (PTT) offer significant potential. However, despite extensive efforts in antimicrobial phototherapy, photosensitizers (PSs) capable of delivering dual PDT/PTT activity against broad-spectrum bacteria remain limited. Herein, we report a PEGylated and brominated amino-hemicyanine derivative ( HoB-PEG ) as a multimodal PDT/PTT agent to effectively eradicate a broad spectrum of clinically relevant pathogens. PEGylation of the hemicyanine core has been shown to address the chronic limitations of organic PSs, such as aggregation in aqueous environments, dark toxicity, and low photostability, thereby enhancing therapeutic outcomes, particularly the PTT effect. In addition to improved PTT outcomes, HoB-PEG generated both type-I and type-II reactive oxygen species (ROS), a critical characteristic that enhances PDT efficacy. HoB-PEG -mediated dual phototherapy resulted in complete inhibition of two Gram-positive ( Enterococcus faecalis and Staphylococcus epidermidis ) and four Gram-negative ( Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli ) bacteria, without remarkable dark toxicity. Notably, the strongest activity was reported in P. aeruginosa, an exceptionally difficult-to-treat pathogen. HoB-PEG also demonstrated potent inhibition of biofilms formed by the same bacterial strains under 640 nm laser irradiation. In contrast, the non-PEGylated analogue ( HoB ) caused severe dark toxicity in most bacteria and fibroblast cells, which limits its practical utility, and showed reduced efficacy in most bacteria. Additionally, HoB-PEG retained sufficient fluorescence emission to enable bacterial imaging. The combined PDT/PTT activity, broad-spectrum antibacterial and antibiofilm efficacy, minimal cytotoxicity, and imaging capability position HoB-PEG as a promising phototheranostic platform for combating resistant bacterial infections.