Targeted Photodynamic Therapy for Multispecies Dental Biofilms Using Liposome Encapsulated p-Toluquinone

Oral infections remain highly prevalent among individuals with limited access to routine dental care. Blue light (BL) offers a promising alternative for managing these infections, but its efficiency is limited without BL-activated photosensitizers. Here, we engineered an ionizable liposome to encapsulate a newly identified BL-activated photosensitizer, p-toluquinone (p-TQ). The resultant p-TQ@Lipo responded to the acidic pH produced by bacteria, facilitating the targeted delivery of the cargo to the pathogens. p-TQ@Lipo had a pH-dependent surface potential change from +29.5 ± 2.1 mV at pH=5, to +8.2 ± 0.1 mV at pH=7, and -6.4 ± 0.5 mV at pH=8. When combined with 405 nm BL at a fluence as low as 27 J/cm², p-TQ@Lipo reduced bacterial load by >99%, with minimal cytotoxicity to human gingival fibroblasts, achieving a remarkable 359-fold improvement in selectivity over free p-TQ. Confocal microscopy validated more efficient delivery of the cargo to Gram-negative than to Gram-positive bacteria, reflecting differences in bacterial surface charges. We then established polymicrobial dental biofilms in vivo and in vitro, comprising BL-sensitive and -refractory and Gram-positive and -negative species. The polymicrobial biofilms were efficiently disrupted on ferret tooth surfaces in an ex vivo infection model and eradicated in an in vivo mouse oral infection model by repeated therapies of p-TQ@Lipo combined with BL, whereas either treatment alone was ineffective. Importantly, the treatment significantly decreased periodontal inflammation and hyperplasia. These findings establish p-TQ@Lipo plus BL as a safe and effective antimicrobial platform with translational potentials for oral infection management.