Gang Zheng

Antimicrobial photodynamic therapy (aPDT) is an alternative to antibiotics that has potential for the treatment of chronic skin wounds, but requires improved, highly selective photosensitizer systems. Rhenium (Re)‐complex‐ and iridium (Ir)‐complex‐based phospholipid conjugates, as PDT‐functional building blocks for liposomes, are presented, and varying structural components and proportion of compounds are explored, including adjusting the cholesterol and polyethylene glycol (PEG)‐lipid contents, incorporating ethylenediaminetetraacetic acid (EDTA)‐lipid, and introducing the cationic lipid 1,2‐dioleoyl‐3‐trimethylammonium propane (DOTAP) to enhance their efficacy and selectivity in aPDT. Ir/Re‐liposomes have nanostructurally enhanced photoactivity compared to monomeric Ir/Re‐lipids. Ir‐liposomes exhibit stronger light absorption and higher emission generation (>threefold) than Re‐liposomes, resulting in superior efficacy against Staphylococcus aureus while maintaining better tolerability toward host cells. Formulations with higher cholesterol (40 mol%) and PEG‐lipid (5%) content demonstrate increased potency against S. aureus . The incorporation of EDTA‐lipid significantly enhances aPDT efficacy but also increases toxicity toward host cells. Incorporation of DOTAP alters the nanoparticles’ surface charge, potentially improving their interaction with bacterial walls, but negatively impacts their stability, leading to aggregation of the nanoparticles. Ir‐HC demonstrates ideal characteristics (effectiveness, selectivity, and stability) for aPDT under the tested conditions, indicating the importance of the structural design of Re‐ and Ir‐complex liposomes for their selectivity in aPDT.