Engineered BioAIE photosensitizer from natural cryptolepine: Amplifying type I/II ROS for photodynamic eradication of...

The escalating threat of antimicrobial resistance (AMR) necessitates urgent development of novel antibacterial agents. Photodynamic therapy (PDT) emerges as a promising alternative strategy due to its non-invasiveness and low resistance development risk. And natural products provide ideal scaffolds for photosensitizer (PS) design owing to inherent bioactivity and biocompatibility. Herein, we reported a structurally modified natural products derived aggregation-induced emission photosensitizer (BioAIE-PS), TPA-CRY, engineered from the natural alkaloid cryptolepine (CRY) for combating bacterial infections and biofilms. This molecular redesign successfully overcame the detrimental aggregation-caused quenching (ACQ) effect and weak reactive oxygen species (ROS) generation intrinsic to native CRY. Notably, upon photoexcitation, TPA-CRY demonstrated substantially enhanced ROS production and superior in vitro antibacterial efficacy compared to its parent compound CRY. Furthermore, it exhibited potent activity against both bacterial biofilms and persister cells. Mechanistic investigations elucidated that bacterial eradication occurs through disruption of membrane integrity, leakage of cellular contents, and ROS-mediated oxidative damage. Crucially, significant in vivo therapeutic efficacy was validated in a murine wound infection model. This work not only validates the substantial potential of TPA-CRY in photodynamic antibacterial therapy but also provides compelling evidence for the rational development of BioAIE-PSs via structural modification of ACQ-type natural products.