Dual-targeting nanotherapy disrupts fungal-bacterial synergy to reprogram inflammatory microenvironments in periodontitis.

Conventional anti-biofilm strategies for periodontitis predominantly focus on bacterial populations, often inadvertently facilitating the resurgence of fungi and aggravating the persistence of biofilms. Here, we report a pH-responsive copper-gallic acid core-shell nanoplatform (CGC@HSAF NP) that eradicates drug-resistant fungal-bacterial biofilms through cross-kingdom synergy, marking a significant advancement over traditional species-specific methodologies. The calcium carbonate shell facilitates an acid-triggered release of the antifungal agent HSAF, which selectively disrupts fungal membranes by inhibiting ceramide synthase. This mechanism not only fractures the biofilm scaffolds but also preserves the viability of dental follicle stem cells (113 % viability compared to only 2 % for free HSAF). Such disruption creates penetration channels for bactericidal Cu2+ ions, leading to significantly enhanced biofilm removal efficacy compared to monotherapy approaches. Importantly, this dual microbial annihilation effectively halts the metabolic cross-feeding that drives biofilm reformation, thereby addressing the persistent kill-recolonize cycle that plagues existing treatments. Concurrently, gallic acid serves as a potent scavenger of reactive oxygen and nitrogen species and mitigates pro-inflammatory cytokine production, thereby remodeling the pathogenic microenvironment favorably. In a rat model of periodontitis, when delivered via a thermosensitive hydrogel, the CGC@HSAF NPs not only eliminated biofilms but also stimulated alveolar bone regeneration. This work redefines the design of antimicrobial agents by emphasizing the disruption of ecological networks rather than merely targeting isolated species, heralding a novel paradigm in the battle against biofilm-associated infections.