Flexible Modulation of Cellular Activities with Cationic Photosensitizers: Insights of Alkyl Chain Length on Reactive Oxygen Species Antimicrobial Mechanisms.

Cationic photosensitizers have good binding ability with negatively charged bacteria and fungi, exhibiting broad potential for use in antimicrobial photodynamic therapy (aPDT). However, cationic photosensitizers often display unsatisfactory transkingdom selectivity between mammalian cells and pathogens, especially for eukaryotic fungi. It is unclear which biomolecular sites may be more efficient for photodynamic damage, owing to the lack of systematic research with the same photosensitizer system. Herein, a series of cationic aggregation-induced emission (AIE) derivatives (CABs) (using berberine (BBR) as the photosensitizers core) with different length alkyl chains were successfully designed and synthetized for flexible modulation of cellular activities. The BBR core can efficiently produce reactive oxygen species (ROS) and achieve high-performance aPDT in a physiological environment. Through the precise regulation of alkyl chain length, different bindings, localizations, and photodynamic killing effects of CABs were achieved and investigated systematically among bacteria, fungi, and mammalian cells. It was found that intracellular active substances (DNA and protein), not membranes, were more efficient damage sites of aPDT. Moderate length alkyl chains enabled CABs to effectively kill Gram-negative bacteria and fungi with light, while still maintaining excellent mammalian cell and blood compatibility, which was further proven in extended in vitro and in vivo aPDT experiments. This study is expected to provide systematic theoretical and strategic research guidance for the construction of high-performance cationic photosensitizers with good transkingdom selectivity. This article is protected by copyright. All rights reserved.