Abstract Precision antimicrobial delivery at infection sites is limited by uncontrolled drug leakage under physiological conditions and mechanical fragility under repeated loading. These limitations undermine therapeutic efficacy while imposing off-target toxicity. Here, we introduce a pH-gated antimicrobial hydrogel engineered to autonomously gate antimicrobial release through conformational switching at constant physiological temperature. By incorporating 1-vinyl imidazole (VIm) as a pH-sensitive comonomer into a mechanically reinforced N-isopropylacrylamide (NIPAAm)–1,4-divinyloxybutane (DVB) network, the resulting NIPAAm–DVB–VIm (NDV) hydrogel adopts a collapsed, low-permeability state at neutral pH that suppresses baseline silver fluoride (AgF) leakage, then undergoes protonation-driven network expansion under pathological acidification to accelerate drug transport without external stimulation. This molecular gating mechanism maintains cytocompatibility in human gingival fibroblasts while achieving pronounced log-scale bacterial reductions against S. mutans and S. aureus compared with non-responsive controls. We systematically evaluated microbiome shifts from dysbiosis toward a more balanced community state in a dental caries model established with patient-derived oral biofilms, where metagenomic profiling revealed that acidic eluates preferentially depleted cariogenic taxa while preserving health-associated commensals, thereby supporting microbiome rebalancing. We extended this microbiome-conscious infection-control strategy to methicillin-resistant S. aureus ( MRSA )-infected full-thickness skin wounds, where topical application of the hydrogel accelerated wound closure, reduced bacterial burden, dampened pro-inflammatory cytokine expression, and partially recovered microbial diversity toward a more balanced ecological state. By coupling pH-autonomous control with mechanical durability, this pH-gated NDV hydrogel provides a strategy for selective, microbiome-conscious infection management across oral and cutaneous pathologies.
Kim et al. (Thu,) studied this question.
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