A "Detachable Polyanionic Protective Shell" Enveloping Photodynamic Cationic Nanoassemblies for Keratitis Treatment

Bacterial keratitis is a rapidly progressive, invasive corneal infection, necessitating the urgent development of more effective antibacterial therapies. Cationic polymers, which exert bactericidal effects by disrupting bacterial membranes, represent a promising candidate; however, their clinical application is limited by cytotoxicity associated with their positive charge. Here, we proposed a "detachable polyanionic protective shell (DPPS)" strategy to shield the positive charges of cationic polymers. Specifically, the quaternary ammonium salt (QAS)-modified polylysine was co-assembled with the photosensitizer chlorin e6 (Ce6) to obtain nanoassemblies (PQC), and then the PQC was encapsulated with polythioctic acid (PTA) to form DPPS, obtaining PQCT with functional adaptability. PQCT maintains a net negative charge under physiological conditions with good biocompatibility. In a bacterial infection environment, the reactive oxygen species (ROS) produced by Ce6 under laser irradiation will cause PTA to break bonds and degrade, DPPS to crack and be removed, the net charge of the nano-assembly to change from negative to positive, and QAS exposed to exert bactericidal functions with ROS. Both in vitro and in vivo studies demonstrated the outstanding antibacterial performance of PQCT after laser irradiation, particularly in the treatment of bacterial keratitis. This work presents a safe and effective strategy for targeted bacterial infection therapy.