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.This study presents an advanced NDV hydrogel system with enhanced mechanical robustness, strong tissue adhesion, and antibacterial functionality. The engineered network architecture enables stable performance under physiological stress conditions. Notably, the pH-responsive NDV3 hydrogel effectively regulates the wound microenvironment, promoting microbiome rebalancing in MRSA-infected wounds and accelerating tissue repair. These findings highlight the potential of NDV hydrogels as a multifunctional platform for next-generation wound healing applications.